CN103864704A - Substituted 2-acetamido-5-aryl-1,2,4-triazolones and use thereof - Google Patents

Substituted 2-acetamido-5-aryl-1,2,4-triazolones and use thereof Download PDF

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CN103864704A
CN103864704A CN201410089595.2A CN201410089595A CN103864704A CN 103864704 A CN103864704 A CN 103864704A CN 201410089595 A CN201410089595 A CN 201410089595A CN 103864704 A CN103864704 A CN 103864704A
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hydrogen
methyl
compound
mmol
trifluoromethyl
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U.布吕格迈尔
C.菲斯特纳
V.盖斯
J.克尔德尼希
A.克恩
M.德尔贝克
P.科尔克霍夫
A.克雷奇默
E.波克
C.施梅克
H.特吕贝尔
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Bayer Pharma AG
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Abstract

The present application relates to new, substituted 2-acetamido-5-aryl-1,2,4-triazolones, to processes for preparing them, to their use alone or in combinations for the treatment and/or prevention of diseases and also to their use for the production of medicaments for the treatment and/or prevention of diseases, more particularly for the treatment and/or prevention of cardiovascular disorders.

Description

2-acetamido-5-aryl-1 replacing, 2,4-triazolone and its purposes
The application is divisional application, and its female case is to be the application that March 12, application number in 2010 are 201080021641.5, denomination of invention is " 2-acetamido-5-aryl-1 of replacement, 2,4-triazolone and its purposes " applying date.
The application relates to 2-acetamido-5-aryl-1 new, that replace, 2,4-triazolone, relate to their method of preparation, relate to them separately or the purposes that combines for the purposes treating and/or preventing of disease and relate to their and produce medicine, this medicine is for the treating and/or preventing of disease, treating and/or preventing for cardiovascular disorder more particularly.
The content liquid of human body is subject to various physiology controlling organizations and arranges, and its objective is and keeps content liquid constant (volume homeostasis).During the course, the osmolarity of the filling of the capacity of vascular system and blood plasma carrys out continuous recording by suitable susceptor (pressure receptor and smell receptor).The information exchange that offers the relevant center in brain by these susceptors crosses body fluid and nerve signal regulates drinking behavior and controls the fluid-evacuation via kidney.Peptide hormone antidiuretic hormone (or being called vasopressing) in this process, have Central Position importance [Schrier R.W., Abraham, W.T., new Engl. J. Med. 341, 577-585 (1999)].
Antidiuretic hormone is to produce and be transported to along its nerve process therefrom in the rear pallette of pituitary body (neurohypophysis) in the special internal secretion neurone in nucleus supraopticus and the N. paraventricularis on the wall of third ventricle (hypothalamus).This hormone is released in blood flow according to stimulation there.The minimizing of volume, for example, because acute bleeding, severe are perspired, thirsty or diarrhoea causes for a long time, is to cause the one that the enhancing of hormone gushes to stimulate.On the contrary, due to the increase of intravascular volume, for example, because the fluid increasing immerses, suppress the secretion of antidiuretic hormone.
Antidiuretic hormone applies its major effect by being incorporated into three kinds of acceptors, and these acceptors are classified as V1a, V1b and V2 acceptor and belong to the family of G protein-coupled receptor.V1a acceptor is mainly positioned on the cell of blood vessel smooth muscles tissue.Their activation can cause vasoconstriction, therefore Peripheral resistance and elevation of blood pressure.In addition, V1a acceptor in liver, also can be detected.V1b acceptor (also referred to as V3 acceptor) in central nervous system, can be detected.Together with corticotropin releasing hormone (CRH), antidiuretic hormone regulates the basic and stress induced secretion of thyroliberin (ACTH) via V1b acceptor.V2 acceptor is arranged in distally tubulose epithelium and the epithelium at the collecting tubule of kidney.It is permeable that their activation makes these epithelium.This phenomenon should the introducing in epithelial luminal membrane owing to Aquaporinen (special aquaporin).
Antidiuretic hormone will see more clearly from the importance for absorbing again the urine in kidney for water from the clinical picture of diabetes insipidus, and this symptom is caused by the defect of hormone (for example, due to pituitary body infringement).The patient who meets with this clinical picture can drain urine/24 hour of 20 liters at the most, if they do not substitute hormone.This volume is corresponding to approximately 10% of first urine.Because it for water from urine absorb again for great importance, antidiuretic hormone is also known as vassopressin (ADH, Antidiuretisches Hormon) in synonym mode.In logic, antidiuretic hormone/ADH can cause urinating of increase for the pharmacology restraining effect of the effect of V2 acceptor.But contrary with the effect of other diuretic(s) (thiazides and ring diuretic(s)), V2 receptor antagonist can cause the water excretion increasing, but can not increase significantly electrolytical excretion.This means, by means of V2 antagonist pharmaceuticals, volume homeostasis can be resumed, without affecting in the process of ionogen homeostasis.Therefore, the medicine with V2 antagonistic activity seems to be particularly suitable for health by the treatment of the relevant whole diseases of the excess load of water, but not parallel increase effectively of ionogen.Significant ionogen is as Hyponatri mie(hyponatremia extremely in clinical chemistry) (na concn < 135 mmol/L) can measure; It is that most important ionogen is abnormal in patient in hospital, wherein only has an appointment 5% sickness rate or 250 000 example/years in the U.S..If plasma sodium concentration is reduced to lower than 115 mmol/L, comatose state and dead just coming.
Depend on this underlying cause, between heavy body (hypovol mische), general capacity (euvol mische) and heavy body hyponatremia, have any different.The form of Hyponatri mie that has oedema to form merits attention clinically.Syndromes (SIAD) (for example, after craniocerebral trauma or as the Paraneoplasie in cancer knurl) and the heavy body hyponatremia in liver cirrhosis that this exemplary is on the one hand inappropriate ADH/ antidiuretic hormone secretion, various ephrosis and cardiac insufficiency [De Luca L. et al. am. J. Cardiol. 96(suppl.), 19L-23L (2005)].Especially, although intentionally Insufficient patient-their relative hyponatremia (Hyponatri mie) and heavy body (Hypervol mie)-usually demonstrate antidiuretic hormone level of raising, this is considered result [the Francis G.S. et al. that the general neurohumour disturbing regulates in cardiac insufficiency illness circulation 82, 1724-1729 (1990)].
The neurohormone disturbing regulates and mainly itself is embodied in the lifting of sympatheticotonia and inappropriate activation of renin-angiotensin-aldosterone system.Although these components are on the one hand by beta-blockers be the intrinsic part of the pharmacological treatment of cardiac insufficiency illness now by ACE inhibitor or restraining effect that angiotensin receptor blocker produced on the other hand, but the improper increase of antidiuretic hormone secretion still cannot sufficiently be treated now in the cardiac insufficiency illness of high development.Except retained by the water of V2 acceptor media and the reverse load of relevant with it just increase with regard to unfavorable property h modynamischen result, the vasoconstriction that emptying, the pressure in pulmonary vascular of left ventricle and stroke volume are also adversely subject to V1a-medium affects.In addition, taking the experimental data in animal as basis, for the direct hypertrophy promoter action of cardiac muscle also owing to antidiuretic hormone.Contrary with the kidney effect (it is by the activation institute medium of V2 acceptor) of volumetric expansion, be to trigger by the activation of V1a acceptor for myocardium direct effect.
Because these reasons, suppress antidiuretic hormone for V2 and/or appear to be suitable for the treatment of cardiac insufficiency for the material of the effect of V1a acceptor.Especially, have in conjunction with active compound and should all there is the kidney and the hemodynamic effect that make us desireing for antidiuretic hormone acceptor (V1a and V2), therefore provide especially desirable pattern (Profil) for the treatment of the patient with cardiac insufficiency.Providing of the antidiuretic hormone antagonist of these combinations also appears to hold water, because only reduced and can be had further compensatory increase on antidiuretic hormone discharges with the stimulation of smell receptor with therefore by the volume of V2 receptor blocking institute medium.Therefore, the component of blocking at the same time V1a acceptor does not exist down, the harmful effect of antidiuretic hormone, and for example vasoconstriction and myocardium hypertrophy, can further strengthen [Saghi P. et al., europ. Heart J. 26, 538-543 (2005)].
WO 99/54315 openly has the substituted triazole ketone of neuroprotective activity, and WO 2006/117657 describes the triazolone derivative as antiphlogistic drug.In addition, EP 503 548-A1 and EP 587 134-A2 have required cyclic urea derivatives and they purposes for the treatment of thrombosis disease.Triazolinthione as the replacement of ion channel modulators has been disclosed in WO 2005/097112.WO 2007/134862 has described as imidazoles-2-ketone of the replacement of the antidiuretic hormone receptor antagonist of the treatment of cardiovascular disorder and 1,2,4-triazolone.
The object of this invention is to provide novel cpd, they are as two V1a/V2 receptor antagonists effective, that select and itself be suitable for treating and/or preventing of disease, are more particularly suitable for treating and/or preventing of cardiovascular diseases.
The invention provides the compound of general formula (I):
Figure 177451DEST_PATH_IMAGE001
(I),
Wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
In formula
* be to be connected to R 3on link position,
R 6Ahydrogen, (C 1-C 4) alkyl or trifluoromethyl,
R 6Bhydrogen or (C 1-C 4) alkyl,
R 7Ahydrogen, (C 1-C 4) alkyl or trifluoromethyl,
R 7Bhydrogen or (C 1-C 4) alkyl,
Q is CH or N,
R 1(C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl or (C 3-C 7) cycloalkyl,
Wherein (C 1-C 6) alkyl, (C 2-C 6) alkenyl and (C 2-C 6) alkynyl can replace by 1-3 substituting group, this substituting group is independently from each other deuterium, halogen, cyano group, oxo, hydroxyl, trifluoromethyl, (C 3-C 7) cycloalkyl, (C 1-C 6) alkoxyl group, trifluoromethoxy and phenyl,
Wherein (C 3-C 7) cycloalkyl can be independently from each other (C by 1 or 2 1-C 4) alkyl, oxo, hydroxyl, (C 1-C 4) substituting group in alkoxyl group and amino replaces,
With
Wherein (C 1-C 6) alkoxyl group can be independently from each other amino, hydroxyl, (C by 1 or 2 1-C 4) alkoxyl group, hydroxycarbonyl group and (C 1-C 4) substituting group in alkoxy carbonyl replaces,
With
Wherein phenyl can be replaced by 1-3 substituting group, and this substituting group is independently from each other halogen, cyano group, nitro, (C 1-C 4) alkyl, trifluoromethyl, hydroxyl, methylol, (C 1-C 4) alkoxyl group, trifluoromethoxy, (C 1-C 4) alkoxy methyl, hydroxycarbonyl group, (C 1-C 4) alkoxy carbonyl, aminocarboxyl, single (C 1-C 4) alkyl amino-carbonyl and two-(C 1-C 4) alkyl amino-carbonyl,
With
Wherein (C 3-C 7) cycloalkyl can be independently from each other fluorine, (C by 1 or 2 1-C 4) alkyl, (C 1-C 4) alkoxyl group, hydroxyl, the substituting group in amino and oxo replaces,
R 2benzothienyl, phenyl, thienyl or furyl,
Wherein benzothienyl, phenyl, thienyl and furyl can be independently from each other halogen, cyano group, nitro, (C by 1-3 1-C 4) alkyl, trifluoromethyl, hydroxyl, (C 1-C 4) substituting group in alkoxyl group and trifluoromethoxy replaces,
R 3trifluoromethyl, hydroxyl, trifluoromethoxy, (C 1-C 4) alkoxyl group, (C 3-C 7) cycloalkyloxy, nitro, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21,-O-SO 2-NR 24r 25， – NR 26-SO 2-NR 27r 28or-NR 30r 31,
Wherein
R 8hydrogen or (C 1-C 4) alkyl,
R 9hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 8and R 9together with the atom being connected to them, form 5-to 7-element heterocycle,
Wherein this 5-to 7-element heterocycle can be independently from each other fluorine, (C 1-C 4) in alkyl and trifluoromethyl 1 or 2 substituting groups replace,
R 10hydrogen or (C 1-C 4) alkyl,
R 11(C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 10and R 11together with the atom being connected to them, form 5-to 7-element heterocycle,
Wherein this 5-to 7-element heterocycle can be independently from each other fluorine, (C 1-C 4) in alkyl and trifluoromethyl 1 or 2 substituting groups replace,
R 12hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 13hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 12and R 13together with the nitrogen-atoms being keyed to them, form 4-to 7-element heterocycle,
Wherein this 4-to 7-element heterocycle can be independently from each other fluorine, oxo, hydroxyl, (C 1-C 4) in alkyl and trifluoromethyl 1 or 2 substituting groups replace,
R 14hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 15hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 14and R 15together with the nitrogen-atoms being keyed to them, form 4-to 7-element heterocycle,
Wherein this 4-to 7-element heterocycle can be independently from each other fluorine, oxo, hydroxyl, (C 1-C 4) in alkyl and trifluoromethyl 1 or 2 substituting groups replace,
R 16hydrogen or (C 1-C 4) alkyl,
R 17hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 18hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 5-to 7-element heterocycle,
Wherein this 5-to 7-element heterocycle can be independently from each other fluorine, trifluoromethyl and (C 1-C 4) in alkyl 1 or 2 substituting groups replace,
Or
R 17and R 18together with the nitrogen-atoms being keyed to them, form 4-to 7-element heterocycle,
Wherein this 4-to 7-element heterocycle can be independently from each other fluorine, oxo, hydroxyl, (C 1-C 4) in alkyl and trifluoromethyl 1 or 2 substituting groups replace,
R 19hydrogen or (C 1-C 4) alkyl,
R 20(C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 19and R 20together with the atom being connected to them, form 5-to 7-element heterocycle,
Wherein this 5-to 7-element heterocycle can be independently from each other fluorine, (C 1-C 4) in alkyl and trifluoromethyl 1 or 2 substituting groups replace,
N is numeral 0,1 or 2,
R 21hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 24hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 25hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 24and R 25together with the nitrogen-atoms being keyed to them, form 4-to 7-element heterocycle,
Wherein this 4-to 7-element heterocycle can be independently from each other fluorine, oxo, hydroxyl, (C 1-C 4) in alkyl and trifluoromethyl 1 or 2 substituting groups replace,
R 26hydrogen or (C 1-C 4) alkyl,
R 27hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 28hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 26and R 27together with the nitrogen-atoms being keyed to them, form 5-to 7-element heterocycle,
Wherein this 5-to 7-element heterocycle can be independently from each other fluorine, trifluoromethyl and (C 1-C 4) in alkyl 1 or 2 substituting groups replace,
Or
R 27and R 28together with the nitrogen-atoms being keyed to them, form 4-to 7-element heterocycle,
Wherein this 4-to 7-element heterocycle can be independently from each other fluorine, oxo, hydroxyl and (C 1-C 4) in alkyl 1 or 2 substituting groups replace,
R 30hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 31(C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 30and R 31together with the nitrogen-atoms being keyed to them, form 4-to 7-element heterocycle,
Wherein this 4-to 7-element heterocycle can be independently from each other fluorine, oxo, hydroxyl, (C 1-C 4) in alkyl and trifluoromethyl 1 or 2 substituting groups replace,
R 4phenyl, naphthyl or 5-to 10-member heteroaryl,
Wherein phenyl, naphthyl and 5-to 10-member heteroaryl can be independently from each other halogen, cyano group, nitro, (C 1-C 4) alkyl, difluoromethyl, trifluoromethyl, hydroxyl, (C 1-C 4) alkoxyl group, the substituting group of the 1-3 in difluoro-methoxy and trifluoromethoxy replaces,
R 5hydrogen, deuterium, trifluoromethyl or (C 1-C 4) alkyl,
R 29hydrogen or (C 1-C 4) alkyl,
And their salt, solvate, and the solvate of salt.
Compound according to the present invention is the compound of general formula (I) and their salt, solvate, and the solvate of this salt; By the compound of the included general formula the following describes of general formula (1), and their salt, solvate, and the solvate of this salt; And conduct work embodiment below illustrated and by the included compound of general formula (I), and their salt, solvate, and the solvate of this salt; As long as be not salt already by the included compound the following describes of general formula (I), solvate, and the solvate of this salt.
Depend on their structure, can exist with stereoisomeric forms in any ratio (enantiomer, diastereomer) according to compound of the present invention.Therefore the present invention comprises enantiomer or diastereomer and their mixture separately.From this type of mixture of enantiomer and/or diastereomer, can separate in known manner the uniform composition of stereoisomerism.
As long as can exist with tautomeric form according to compound of the present invention, the present invention includes so whole tautomeric forms.
Preferred in background of the present invention saltit is the physiologically acceptable salt of the compounds of this invention.What also comprise is such salt, it-itself be not suitable for medicinal application-but for example can be used for separation or the purification of the compounds of this invention.
The physiological acceptable salt of the compounds of this invention comprises the acid-adducting salt of mineral acid, carboxylic acid and sulfonic acid, and example is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methanesulfonic, ethane sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartrate, oxysuccinic acid, citric acid, fumaric acid, toxilic acid and benzoic salt.
The physiological acceptable salt of the compounds of this invention also comprises the salt forming with conventional alkali, for example and preferably, and an alkali metal salt (for example sodium and sylvite), alkaline earth salt (for example calcium and magnesium salts) and from ammonia or there is the derivative ammonium salt of organic amine of 1-16 C atom, for example and preferably, ethylamine, diethylamide, triethylamine, ethyl diisopropyl amine, monoethanolamine, diethanolamine, trolamine, dicyclohexylamine, dimethylaminoethanol, PROCAINE HCL, PHARMA GRADE, dibenzyl amine n-methylmorpholine, arginine, Methionin, quadrol and n-methyl piperidine.
In scope of the present invention solvateby forming the compounds of this invention of those forms of solid-state or liquid title complex with solvent molecule coordination.Hydrate is a kind of solvate of particular form, and wherein this coordination is between water.In background of the present invention, preferred solvate is hydrate.
In addition, the present invention also comprises prodrug of the present invention.Term " prodrug " comprises such compound, but itself biological activity or abiotic activity, but in residence time in vivo, they are converted (for example metabolism or hydrolysis) and become compound of the present invention.
In background of the present invention, unless otherwise mentioned, otherwise this substituting group has following definition:
In scope of the present invention alkyllinearity or the branched-chain alkyl with 1-6 or 1-4 carbon atom.For example and preferably, it comprise following these: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, 1-methyl-propyl, the tertiary butyl, n-pentyl, isopentyl, 1-ethyl propyl, 1-methyl butyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-methyl amyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 3,3-dimethylbutyl, 1-ethyl-butyl and 2-ethyl-butyl.
Within the scope of the invention cycloalkylit is the monocycle saturated alkyl with 3-7 or 3-6 carbon atom.For example and preferably, it comprises following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
In scope of the present invention alkenyllinearity or the branched chain thiazolinyl with 2-6 carbon atom and one or two pair of key.Preferably there is the two straight chains of key of 2-4 carbon atom and or the alkenyl of branching.For example and preferably, it comprises following: vinyl, allyl group, pseudoallyl and n-but-2-ene-1-base.
In scope of the present invention alkynyllinearity or the branching alkynyl with 2-6 carbon atom and three key.For example and preferably, it comprises following groups: ethynyl, positive third-1-alkynes-1-base, positive third-2-alkynes-1-base, positive fourth-2-alkynes-1-base and positive fourth-3-alkynes-1-base.
In scope of the present invention alkoxyl grouplinearity or the branched alkoxy with 1-6 or 1-4 carbon atom.For example and preferably, it comprises following groups: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, 1-methyl propoxy-, n-butoxy, isobutoxy and tert.-butoxy.
Within the scope of the invention cycloalkyloxyit is the monocycle saturated cyclic alkyls with 3-7 carbon atom connecting via Sauerstoffatom.For example and preferably, it comprises following groups: ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy and ring oxygen base in heptan.
Within the scope of the invention alkoxy carbonylthere is linearity or the branched alkoxy of 1-6 carbon atom and be connected in the carbonyl on oxygen.For example and preferably, it comprises following: methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, isopropoxy carbonyl and tert-butoxycarbonyl.
Within the scope of the invention alkyl monosubstituted amino carbonylbe connect via carbonyl and there is linearity or the substituent amino of branched-chain alkyl containing 1-4 carbon atom.For example and preferably, it comprises following groups: methylamino carbonyl, ethylamino carbonyl, n-propyl aminocarboxyl, isopropylamino carbonyl, normal-butyl aminocarboxyl and tertiary butyl aminocarboxyl.
Within the scope of the invention dialkyl amino carbonylamino that connect and that there is 2 identical or different linearities or branched-chain alkyl substituting group (it respectively has 1-4 carbon atom) via carbonyl.For example and preferably, it comprises following groups: N, N-dimethylamino carbonyl, N, N-diethylamino carbonyl, N-ethyl-N-methylamino carbonyl, N-methyl-N-n-propyl aminocarboxyl, N-normal-butyl-N-methylamino carbonyl and the N-tertiary butyl-N-methylamino carbonyl.
Within the scope of the invention heterocyclebe the saturated or part unsaturated heterocycle altogether with 4-7 ring Atom, it comprises heteroatoms in one to three ring being selected from N, O and/or S series, and via carbon atom in a ring or optionally in a ring nitrogen-atoms connect.For example, it comprises following groups: azetidinyl, and pyrrolidyl, piperidyl, nitrogen heterocyclic heptyl, pyrazolidyl, imidazolidyl, piperazinyl, tetrahydro-pyrimidine base,
Figure 267767DEST_PATH_IMAGE002
oxazolidinyl, morpholinyl, thio-morpholinyl, diazacyclo heptyl, tetrahydrofuran base, THP trtrahydropyranyl,
Figure 449350DEST_PATH_IMAGE002
piperazine alkyl (oxazinanyl), oxaza heptyl,
2-oxo-pyrrolidine-1-base, 2-oxo-piperidine-1-base, 2-oxo azepan-1-base, 2-oxo-imidazole alkane-1-base, 2-oxo-1,3-
Figure 717651DEST_PATH_IMAGE002
azoles alkane-3-base, 2-oxo tetrahydropyrimidine-1 (2H)-Ji, 2-oxo-1,3-
Figure 617474DEST_PATH_IMAGE002
piperazine alkane-3-base, 2-oxo-1,3-azepan-1-base, 2-oxo-1,3-oxaza heptane-3-base, 2,3-dihydro-1H-pyrroles-1-base, 2-oxo-2,3-dihydro-1H-pyrroles-1-base, 2-oxo-2,5-dihydro-1H-pyrroles-1-base, 2-oxo-1,3-
Figure 183585DEST_PATH_IMAGE002
oxazolidinyl-3-base, 2-oxo-1,3-
Figure 281991DEST_PATH_IMAGE002
azoles-3 (2H)-Ji, 2-oxo-imidazole alkane-1-base, 2-oxo-2, 3-dihydro-1H-imidazoles-1-base, 1, 1-dioxy base (Dioxido)-1, 2-thiazolidine-2-Ji, 1, 1-dioxy base (Dioxido)-1, 2 – thiazan (thiazinan)-2-bases, 1, 1-dioxy base (Dioxido)-1, 2-sulfur nitrogen heterocycle heptane-2-base, 1, 1-dioxy base (Dioxido)-1, 2, 5-thiadiazolidine-2-base, 1, 1-dioxy base (Dioxido)-1, 2, 6-thiadiazine alkane (thiadiazinan)-2-base and 1, 1-dioxy base (Dioxido)-1, 2, 7-thia Diazesuberane-2-base.Preferably azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, diazacyclo heptyl, oxaza heptyl, 2-oxo-imidazole alkane-1-base, 2-oxo-2,3-dihydro-1H-pyrroles-1-base, 2-oxo-2,5-dihydro-1H-pyrroles-1-base, 2-oxo-1,3-
Figure 908144DEST_PATH_IMAGE002
azoles alkane-3-base, 1,1-dioxy base (Dioxido)-1,2,5-thiadiazolidine-2-base, 2-oxo tetrahydropyrimidine-1 (2H)-Ji, 2-oxo-1,3-
Figure 29684DEST_PATH_IMAGE002
piperazine alkane-3-base, 2-oxo-1,3-Diazesuberane-1-base and 2-oxo-1,3-oxaza heptane-3-base.
Within the scope of the invention heteroarylto there is altogether the monocycle of 5-10 ring Atom or bicyclic aromatic heterocycle (heteroaromatic) optionally, it comprises heteroatoms in three the identical or different rings at the most that are selected from N, O and/or S series, and via carbon atom in a ring or optionally via nitrogen-atoms connection in a ring.For example, it comprises following groups: furyl, and pyrryl, thienyl, pyrazolyl, imidazolyl, thiazolyl, azoles base, different
Figure 368710DEST_PATH_IMAGE002
azoles base, isothiazolyl, triazolyl,
Figure 228081DEST_PATH_IMAGE002
di azoly, thiadiazolyl group, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzo
Figure 836917DEST_PATH_IMAGE002
azoles base, benzothiazolyl, benzotriazole base, indyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolyl, quinoxalinyl, 2，3-benzodiazine base, pyrazolo [3,4-b] pyridyl.Preferably there is heteroatomic monocycle in three rings at the most that are selected from N, O and/or S series 5-or 6-person's heteroaryl, for example furyl, thienyl, thiazolyl,
Figure 744830DEST_PATH_IMAGE002
azoles base, isothiazolyl, different
Figure 583209DEST_PATH_IMAGE002
azoles base, pyrazolyl, imidazolyl, triazolyl,
Figure 551165DEST_PATH_IMAGE002
di azoly, thiadiazolyl group, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl.
In scope of the present invention halogencomprise fluorine, chlorine, bromine and iodine.Preferably chlorine or fluorine.
Within the scope of the invention oxo baseto be connected to the Sauerstoffatom on carbon atom via two keys.
If the group in compound of the present invention is substituted, this group, unless otherwise mentioned, can be substituted one or many.In background of the present invention, be applicable to, for the whole groups that occur more than once, their definition is irrelevant each other.By one, it is preferred that two or three identical or different substituting groups replace.Very particularly preferably by a substituent replacement.
The compound of general formula (I-B) preferably in background of the present invention
Figure 709614DEST_PATH_IMAGE003
(I-B),
Wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen, (C 1-C 4) alkyl or trifluoromethyl,
R 6Bhydrogen or (C 1-C 4) alkyl,
R 7Ahydrogen, (C 1-C 4) alkyl or trifluoromethyl,
R 7Bhydrogen or (C 1-C 4) alkyl,
R 1(C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl or (C 3-C 7) cycloalkyl,
Wherein (C 1-C 6) alkyl, (C 2-C 6) alkenyl and (C 2-C 6) alkynyl can replace by 1-3 substituting group, this substituting group is independently from each other halogen, cyano group, oxo, hydroxyl, trifluoromethyl, (C 3-C 7) cycloalkyl, (C 1-C 6) alkoxyl group, trifluoromethoxy and phenyl,
Wherein (C 3-C 7) cycloalkyl can be independently from each other (C 1-C 4) alkyl, oxo, hydroxyl, (C 1-C 4) 1 or 2 substituting group in alkoxyl group and amino replaces,
With
Wherein (C 1-C 6) alkoxyl group can be independently from each other amino, hydroxyl, (C 1-C 4) alkoxyl group, hydroxycarbonyl group and (C 1-C 4) 1 or 2 substituting group in alkoxy carbonyl replaces,
With
Wherein phenyl can be independently from each other halogen, cyano group, nitro, (C 1-C 4) alkyl, trifluoromethyl, hydroxyl, methylol, (C 1-C 4) alkoxyl group, trifluoromethoxy, (C 1-C 4) alkoxy methyl, hydroxycarbonyl group, (C 1-C 4) alkoxy carbonyl, aminocarboxyl, single (C 1-C 4) alkyl amino-carbonyl and two-(C 1-C 4) 1-3 substituting group in alkyl amino-carbonyl replace,
With
Wherein (C 3-C 7) cycloalkyl can be independently from each other fluorine, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, hydroxyl, 1 or 2 substituting group in amino and oxo replaces,
R 2phenyl, thienyl or furyl,
Wherein phenyl, thienyl and furyl can be independently from each other halogen, cyano group, nitro, (C 1-C 4) alkyl, trifluoromethyl, hydroxyl, (C 1-C 4) 1-3 substituting group in alkoxyl group and trifluoromethoxy replace,
R 3trifluoromethyl, hydroxyl, nitro, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20or-S (=O) nr 21,
Wherein
R 8hydrogen or (C 1-C 4) alkyl,
R 9hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 10hydrogen or (C 1-C 4) alkyl,
R 11(C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 12hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 13hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 12and R 13together with the nitrogen-atoms being keyed to them, form 4-to 7-element heterocycle,
Wherein this 4-to 7-element heterocycle can be independently from each other fluorine, oxo, hydroxyl and (C 1-C 4) in alkyl 1 or 2 substituting groups replace,
R 14hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 15hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 14and R 15together with the nitrogen-atoms being keyed to them, form 4-to 7-element heterocycle,
Wherein this 4-to 7-element heterocycle can be independently from each other fluorine, oxo, hydroxyl and (C 1-C 4) in alkyl 1 or 2 substituting groups replace,
R 16hydrogen or (C 1-C 4) alkyl,
R 17hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 18hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 5-to 7-element heterocycle,
Wherein this 5-to 7-element heterocycle can be independently from each other fluorine and (C 1-C 4) in alkyl 1 or 2 substituting groups replace,
Or
R 17and R 18together with the nitrogen-atoms being keyed to them, form 4-to 7-element heterocycle,
Wherein this 4-to 7-element heterocycle can be independently from each other fluorine, oxo, hydroxyl and (C 1-C 4) in alkyl 1 or 2 substituting groups replace,
R 19hydrogen or (C 1-C 4) alkyl,
R 20(C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 19and R 20together with the atom being connected to them, form 5-to 7-element heterocycle,
Wherein this 5-to 7-element heterocycle can be independently from each other fluorine and (C 1-C 4) in alkyl 1 or 2 substituting groups replace,
N is numeral 0,1 or 2,
R 21hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 4phenyl, naphthyl or 5-to 10-member heteroaryl,
Wherein phenyl, naphthyl and 5-to 10-member heteroaryl can be independently from each other halogen, cyano group, nitro, (C 1-C 4) alkyl, difluoromethyl, trifluoromethyl, hydroxyl, (C 1-C 4) alkoxyl group, the substituting group of the 1-3 in difluoro-methoxy and trifluoromethoxy replaces,
R 5hydrogen, trifluoromethyl or (C 1-C 4) alkyl,
And their salt, solvate, and the solvate of salt.
The compound of general formula (I) preferably within the scope of the invention, wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen, methyl or trifluoromethyl,
R 6Bhydrogen or methyl,
R 7Ahydrogen, methyl or trifluoromethyl,
R 7Bhydrogen or methyl,
Q is CH or N,
R 1(C 1-C 6) alkyl, (C 2-C 6) alkenyl or (C 3-C 6) cycloalkyl,
Wherein (C 1-C 6) alkyl and (C 2-C 6) alkenyl can be independently from each other fluorine, chlorine, cyano group, oxo, hydroxyl, trifluoromethyl, (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the substituting group of the 1-3 in trifluoromethoxy and phenyl replaces,
Wherein (C 3-C 6) cycloalkyl can be independently from each other methyl, ethyl, oxo, hydroxyl, methoxyl group, 1 or 2 substituting group in oxyethyl group and amino replaces,
With
Wherein phenyl can be selected from fluorine, chlorine, and cyano group, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group, trifluoromethoxy, methoxymethyl, ethoxyl methyl, hydroxycarbonyl group, methoxycarbonyl, the substituting group in ethoxy carbonyl and aminocarboxyl replaces,
With
Wherein (C 3-C 6) cycloalkyl can be independently from each other fluorine, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, 1 or 2 substituting group in amino and oxo replaces,
R 2thionaphthene-2-base, phenyl or thienyl,
Wherein thionaphthene-2-base, phenyl and thienyl can be independently from each other fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxyl, methoxyl group, 1 or 2 substituting group in oxyethyl group and trifluoromethoxy replaces,
R 3trifluoromethyl, hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21,-O-SO 2-NR 24r 25huo – NR 26-SO 2-NR 27r 28-,
Wherein
R 8hydrogen or methyl,
R 9(C 1-C 4) alkyl,
Or
R 8and R 9together with the atom being connected to them, form 5-to 7-element heterocycle,
R 10hydrogen or methyl,
R 11(C 1-C 4) alkyl,
Or
R 10and R 11together with the atom being connected to them, form 5-to 7-element heterocycle,
R 12(C 1-C 4) alkyl,
R 13(C 1-C 4) alkyl,
R 14hydrogen or (C 1-C 4) alkyl,
R 15hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 14and R 15together with the nitrogen-atoms being keyed to them, form 4-to 7-element heterocycle,
R 16hydrogen or (C 1-C 4) alkyl,
R 17hydrogen or (C 1-C 4) alkyl,
R 18hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 5-to 7-element heterocycle,
R 19hydrogen or methyl,
R 20(C 1-C 4) alkyl,
Or
R 19and R 20together with the atom being connected to them, form 5-to 7-element heterocycle,
N is numeral 0,1 or 2,
R 21(C 1-C 4) alkyl,
R 24hydrogen or methyl,
R 25hydrogen or methyl,
R 26hydrogen or methyl,
R 27hydrogen or (C 1-C 4) alkyl,
R 28hydrogen or (C 1-C 4) alkyl,
Or
R 26and R 27together with the nitrogen-atoms being keyed to them, form 5-to 7-element heterocycle,
R 4phenyl,
Wherein phenyl can be independently from each other fluorine, chlorine, and cyano group, methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxyl, methoxyl group, oxyethyl group, the substituting group of the 1-3 in difluoro-methoxy and trifluoromethoxy replaces,
R 5hydrogen, deuterium, trifluoromethyl, methyl or ethyl,
R 29hydrogen or methyl,
And their salt, solvate, and the solvate of salt.
The compound of general formula (I-B) preferably within the scope of the invention, wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
In formula
* be to be connected to R 3on link position,
R 6Ahydrogen, methyl or trifluoromethyl,
R 6Bhydrogen or methyl,
R 7Ahydrogen, methyl or trifluoromethyl,
R 7Bhydrogen or methyl,
R 1(C 1-C 6) alkyl, (C 2-C 6) alkenyl or (C 3-C 6) cycloalkyl,
Wherein (C 1-C 6) alkyl and (C 2-C 6) alkenyl can be independently from each other fluorine, chlorine, cyano group, oxo, hydroxyl, trifluoromethyl, (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the substituting group of the 1-3 in trifluoromethoxy and phenyl replaces,
Wherein (C 3-C 6) cycloalkyl can be independently from each other methyl, ethyl, oxo, hydroxyl, methoxyl group, 1 or 2 substituting group in oxyethyl group and amino replaces,
With
Wherein phenyl can be selected from fluorine, chlorine, and cyano group, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group, trifluoromethoxy, methoxymethyl, ethoxyl methyl, hydroxycarbonyl group, methoxycarbonyl, the substituting group in ethoxy carbonyl and aminocarboxyl replaces,
With
Wherein (C 3-C 6) cycloalkyl can be independently from each other fluorine, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, 1 or 2 substituting group in amino and oxo replaces,
R 2phenyl or thienyl,
Wherein phenyl and thienyl can be independently from each other fluorine, chlorine, and methyl, ethyl, trifluoromethyl, hydroxyl, methoxyl group, 1 or 2 substituting group in oxyethyl group and trifluoromethoxy replaces,
R 3trifluoromethyl, hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18or-NR 19-C (=O)-OR 20,
In formula
R 8hydrogen or methyl,
R 9(C 1-C 4) alkyl,
R 10hydrogen or methyl,
R 11(C 1-C 4) alkyl,
R 12(C 1-C 4) alkyl,
R 13(C 1-C 4) alkyl,
R 14hydrogen or (C 1-C 4) alkyl,
R 15hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 14and R 15together with the nitrogen-atoms being keyed to them, form 4 to 6-element heterocycles,
R 16hydrogen or (C 1-C 4) alkyl,
R 17hydrogen or (C 1-C 4) alkyl,
R 18hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 17and R 18together with the nitrogen-atoms being keyed to them, form 4 to 6-element heterocycles,
R 19hydrogen or methyl,
R 20(C 1-C 4) alkyl,
Or
R 19and R 20together with the atom being connected to them, form 5-or 6-element heterocycle,
R 4phenyl,
Wherein phenyl can be independently from each other fluorine, chlorine, and cyano group, methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxyl, methoxyl group, oxyethyl group, the substituting group of the 1-3 in difluoro-methoxy and trifluoromethoxy replaces,
R 5hydrogen, trifluoromethyl, methyl or ethyl,
And their salt, solvate, and the solvate of salt.
Particularly preferably be within the scope of the invention the compound of general formula (I), wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen or trifluoromethyl,
R 6Bhydrogen,
R 7Ahydrogen,
R 7Bhydrogen,
Q is N,
R 1(C 2-C 4) alkyl, (C 2-C 4) alkenyl or cyclopropyl,
Wherein (C 2-C 4) alkyl and (C 2-C 4) alkenyl can be independently from each other fluorine, oxo, 1 or 2 substituting group in hydroxyl and trifluoromethyl replaces,
R 2phenyl,
The substituting group that wherein phenyl can be selected from fluorine or chlorine replaces,
R 3hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21or-NR 26-SO 2-NR 27r 28-,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 12methyl,
R 13methyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 2-oxo-imidazole alkane-1-base or 2-oxo tetrahydropyrimidine-1 (2H)-basic ring,
R 19hydrogen,
R 20methyl or ethyl,
Or
R 19and R 20together with the atom being connected to them, form 2-oxo-1,3-
Figure 421218DEST_PATH_IMAGE002
azoles alkane-3-base or 2-oxo-1,3-
Figure 427351DEST_PATH_IMAGE002
piperazine alkane-3-basic ring,
N is numeral 0 or 2,
R 21methyl,
R 26hydrogen,
R 27hydrogen,
R 28hydrogen,
R 4it is the group of following structural formula
Figure 566209DEST_PATH_IMAGE004
Wherein
# is be connected to-C (R 5) (AR 3) tie point on N-,
R 22hydrogen, cyano group, methyl, trifluoromethoxy, fluorine, chlorine, trifluoromethyl and methoxyl group,
R 23hydrogen, cyano group, methyl, trifluoromethoxy, fluorine, chlorine, trifluoromethyl and methoxyl group,
Wherein this radicals R 22and R 23in at least one be not hydrogen,
R 5hydrogen or methyl,
R 29hydrogen,
And their salt, solvate, and the solvate of salt.
Particularly preferably be in addition within the scope of the invention the compound of general formula (I), wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen or trifluoromethyl,
R 6Bhydrogen,
R 7Ahydrogen,
R 7Bhydrogen,
Q is N,
R 1(C 2-C 4) alkyl, (C 2-C 4) alkenyl or cyclopropyl,
Wherein (C 2-C 4) alkyl and (C 2-C 4) alkenyl can be independently from each other fluorine, oxo, 1 or 2 substituting group in hydroxyl and trifluoromethyl replaces,
R 2phenyl,
The substituting group that wherein phenyl can be selected from fluorine or chlorine replaces,
R 3trifluoromethyl, hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21or-NR 26-SO 2-NR 27r 28-,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 12methyl,
R 13methyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 2-oxo-imidazole alkane-1-base or 2-oxo tetrahydropyrimidine-1 (2H)-basic ring,
R 19hydrogen,
R 20methyl or ethyl,
Or
R 19and R 20together with the atom being connected to them, form 2-oxo-1,3-
Figure 697107DEST_PATH_IMAGE002
azoles alkane-3-base or 2-oxo-1,3- piperazine alkane-3-basic ring,
N is numeral 0 or 2,
R 21methyl,
R 26hydrogen,
R 27hydrogen,
R 28hydrogen,
R 4it is the group of following structural formula
Figure 197675DEST_PATH_IMAGE004
Wherein
# is be connected to-C (R 5) (AR 3) tie point on N-,
R 22hydrogen, fluorine, chlorine, trifluoromethyl and methoxyl group,
R 23hydrogen, fluorine, chlorine, trifluoromethyl and methoxyl group,
Wherein this radicals R 22and R 23in at least one be not hydrogen,
R 5hydrogen or methyl,
R 29hydrogen,
And their salt, solvate, and the solvate of salt.
More particularly preferably be within the scope of the invention the compound of general formula (I), wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen or trifluoromethyl,
R 6Bhydrogen,
R 7Ahydrogen,
R 7Bhydrogen,
Q is N,
R 13,3,3-trifluoropropyl-1-alkene-1-base, 3,3,3-trifluoro propyl or 1,1,1-trifluoro propan-2-ol-3-base,
R 2phenyl,
The substituting group that wherein phenyl can be selected from fluorine or chlorine replaces,
R 3hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21or-NR 26-SO 2-NR 27r 28-,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 12methyl,
R 13methyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 2-oxo-imidazole alkane-1-base or 2-oxo tetrahydropyrimidine-1 (2H)-basic ring,
R 19hydrogen,
R 20methyl or ethyl,
Or
R 19and R 20together with the atom being connected to them, form 2-oxo-1,3- azoles alkane-3-base or 2-oxo-1,3- piperazine alkane-3-basic ring,
N is numeral 0 or 2,
R 21methyl,
R 26hydrogen,
R 27hydrogen,
R 28hydrogen,
R 4it is the group of following structural formula
Figure 241352DEST_PATH_IMAGE004
In formula
# is be connected to-C (R 5) (AR 3) connection site on N-,
R 22hydrogen, fluorine, chlorine and trifluoromethyl,
R 23hydrogen, fluorine, chlorine and trifluoromethyl,
Wherein this radicals R 22and R 23in at least one be not hydrogen,
R 5hydrogen or methyl,
R 29hydrogen,
And their salt, solvate, and the solvate of salt.
Particularly preferably be within the scope of the invention the compound of general formula (I-B), wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen or trifluoromethyl,
R 6Bhydrogen,
R 7Ahydrogen,
R 7Bhydrogen,
R 1(C 2-C 4) alkyl, (C 2-C 4) alkenyl or cyclopropyl,
Wherein (C 2-C 4) alkyl and (C 2-C 4) alkenyl can be independently from each other fluorine, hydroxyl, 1 or 2 substituting group in oxo and trifluoromethyl replaces,
R 2phenyl,
The substituting group that wherein phenyl can be selected from fluorine and chlorine replaces,
R 3trifluoromethyl, hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-O-C (=O)-NR 14r 15or-NR 16-C (=O)-NR 17r 18,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
R 4it is the group of following structural formula
Figure 81132DEST_PATH_IMAGE004
Wherein
# is be connected to-C (R 5) (AR 3) link position on N-,
R 22hydrogen, cyano group, methyl, trifluoromethoxy, fluorine, chlorine, trifluoromethyl and methoxyl group,
R 23hydrogen, cyano group, methyl, trifluoromethoxy, fluorine, chlorine, trifluoromethyl and methoxyl group,
Wherein this radicals R 22and R 23in at least one be not hydrogen,
R 5hydrogen or methyl,
And their salt, solvate, and the solvate of salt.
Particularly preferably be in addition within the scope of the invention the compound of general formula (I-B), wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen or trifluoromethyl,
R 6Bhydrogen,
R 7Ahydrogen,
R 7Bhydrogen,
R 1(C 2-C 4) alkyl, (C 2-C 4) alkenyl or cyclopropyl,
Wherein (C 2-C 4) alkyl and (C 2-C 4) alkenyl can be independently from each other fluorine, hydroxyl, 1 or 2 substituting group in oxo and trifluoromethyl replaces,
R 2phenyl,
The substituting group that wherein phenyl can be selected from fluorine and chlorine replaces,
R 3trifluoromethyl, hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-O-C (=O)-NR 14r 15or-NR 16-C (=O)-NR 17r 18,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
R 4it is the group of following structural formula
Figure 624109DEST_PATH_IMAGE004
Wherein
# is be connected to-C (R 5) (AR 3) connection site on N-,
R 22hydrogen, fluorine, chlorine, trifluoromethyl and methoxyl group,
R 23hydrogen, fluorine, chlorine, trifluoromethyl and methoxyl group,
Wherein this radicals R 22and R 23in at least one be not hydrogen,
R 5hydrogen or methyl,
And their salt, solvate, and the solvate of salt.
More particularly preferably be within the scope of the invention the compound of general formula (I-B), wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen or trifluoromethyl,
R 6Bhydrogen,
R 7Ahydrogen,
R 7Bhydrogen,
R 13,3,3-trifluoropropyl-1-alkene-1-base, 3,3,3-trifluoro propyl or 1,1,1-trifluoro propan-2-ol-3-base,
R 2phenyl,
The substituting group that wherein phenyl can be selected from fluorine and chlorine replaces,
R 3hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-O-C (=O)-NR 14r 15or-NR 16-C (=O)-NR 17r 18,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
R 4it is the group of following structural formula
Figure 182129DEST_PATH_IMAGE004
Wherein
# is be connected to-C (R 5) (AR 3) connection site on N-,
R 22hydrogen, fluorine, chlorine or trifluoromethyl,
R 23hydrogen, fluorine, chlorine or trifluoromethyl,
Wherein this radicals R 22and R 23in at least one be not hydrogen,
R 5hydrogen or methyl,
And their salt, solvate, and the solvate of salt.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 2it is p-chloro-phenyl-.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein
R 2phenyl or thienyl,
Wherein phenyl and thienyl can be selected from fluorine, chlorine, and methyl, ethyl, trifluoromethyl, hydroxyl, methoxyl group, the substituting group in oxyethyl group and trifluoromethoxy replaces.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 1it is 3,3,3-trifluoropropyl-1-alkene-1-base.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 1it is 3,3,3-trifluoro propyl.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 1it is 1,1,1-trifluoro propan-2-ol-3-base.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein
R 1(C 2-C 4) alkyl or (C 2-C 4) alkenyl,
Wherein (C 2-C 4) alkyl and (C 2-C 4) alkenyl can be independently from each other fluorine, hydroxyl, 1 or 2 substituting group in oxo and trifluoromethyl replaces.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 1it is cyclopropyl.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein
R 3-O-C (=O)-NR 14r 15or-NR 16-C (=O)-NR 17r 18,
Wherein
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein
R 3be-NR 10-SO 2-R 11,
Wherein
R 10be hydrogen and
R 11methyl or ethyl.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein
R 3hydroxyl or amino.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein
R 3be-NR 16-C (=O)-NR 17r 18or-NR 19-C (=O)-OR 20,
Wherein
R 16and R 17together with the nitrogen-atoms being keyed to them, form 2-oxo-imidazole alkane-1-base or 2-oxo tetrahydropyrimidine-1 (2H)-basic ring,
R 19and R 20together with the atom being connected to them, form 2-oxo-1,3- azoles alkane-3-base or 2-oxo-1,3-
Figure 543633DEST_PATH_IMAGE002
piperazine alkane-3-basic ring.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein
R 3be-NR 16-C (=O)-NR 17r 18or-NR 19-C (=O)-OR 20,
Wherein
R 16and R 17together with the nitrogen-atoms being keyed to them, form 2-oxo-imidazole alkane-1-basic ring,
R 19and R 20together with the atom being connected to them, form 2-oxo-1,3-
Figure 257511DEST_PATH_IMAGE002
azoles alkane-3-basic ring.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein A is-CH 2-CH 2-.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein A is-CH 2-.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein Q is N.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein Q is CH.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 5hydrogen, trifluoromethyl, methyl or ethyl.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 5hydrogen.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 5it is methyl.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 5trifluoromethyl, methyl or ethyl.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 29hydrogen.
It is also preferred that within the scope of the invention the compound of general formula (I), wherein R 29it is methyl.
The group definition providing respectively in the combination separately of group and preferred combination at random by other in conjunction with in group definition substitute, this is independent of with given concrete group is combined.
Very particularly preferably be the two or more combination in above-mentioned preferable range.
The present invention further provides preparation according to the method for general formula of the present invention (I) compound, be characterised in that
The compound of [A] general formula (II)
Figure 37248DEST_PATH_IMAGE005
(II),
Wherein Q, R 1and R 2separately as defined above,
In inert solvent, by the activation of carboxylic acid functional, be coupled on the compound of general formula (III)
(III),
Wherein A, R 3, R 4, R 5and R 29separately as defined above,
Or
The compound of [B] general formula (IV):
Figure 59879DEST_PATH_IMAGE007
(IV),
Wherein Q, R 1and R 2separately as defined above,
In inert solvent, under alkali exists, react with the compound of structure formula V
Figure 882341DEST_PATH_IMAGE008
(V),
Wherein A, R 3, R 4, R 5and R 29respectively above definition freely,
With
X 1leavings group, as halogen, methanesulfonate or tosylate,
Then the compound of gained general formula (I) is optionally used corresponding (i) solvent and/or (ii) alkali or acid change into their solvate, the solvate of salt and/or this salt.
The inert solvent of processing step (II)+(III) → (I) be for example ether as ether, two
Figure 211691DEST_PATH_IMAGE002
alkane, tetrahydrofuran (THF), glycol dimethyl ether or diglyme, hydro carbons is as benzene,toluene,xylene, hexane, hexanaphthene or petroleum fractions, and halohydrocarbon is as methylene dichloride, trichloromethane, tetrachloromethane, 1,2-ethylene dichloride, trieline or chlorobenzene, or other solvent is as acetone, ethyl acetate, acetonitrile, pyridine, dimethyl sulfoxide (DMSO), DMF, N, N '-dimethylpropylene urea (DMPU) or N-Methyl pyrrolidone (NMP).Similarly likely use the mixture of this solvent.Methylene dichloride, tetrahydrofuran (THF), the mixture of dimethyl formamide or these solvents is preferred.
Amidated suitable condensing agent for processing step (II)+(III) → (I) comprises, for example, carbodiimide is as N, N '-diethyl-, N, N '-dipropyl-, N, N '-di-isopropyl-, N, N '-dicyclohexyl carbodiimide (DCC) or N-(3-dimethylamino sec.-propyl)-N '-ethyl-carbodiimide hydrochloride (EDC), phosgene derivative is as N, N '-carbonyl dimidazoles (CDI), 1,2-
Figure 410592DEST_PATH_IMAGE002
azoles compound is as 2-ethyl-5-phenyl-1,2-
Figure 885883DEST_PATH_IMAGE002
azoles
Figure 640213DEST_PATH_IMAGE009
-3 vitriol or the 2-tertiary butyl-5-methyl-different
Figure 642804DEST_PATH_IMAGE002
azoles
Figure 228506DEST_PATH_IMAGE009
perchlorate, acyl amino compound is as 2-oxyethyl group-1-ethoxy carbonyl-1,2-dihydroquinoline, or isobutyl chlorocarbonate, propane phosphonic acid acid anhydride, cyano group phosphonic acids diethyl ester, two-(2-oxo-3- oxazolidinyl) phosphoryl chloride, benzotriazole-1-base oxygen base-tri-(dimethylamino) phosphorus hexafluorophosphate, benzotriazole-1-base oxygen base-tri-(pyrrolidino) phosphorus
Figure 988149DEST_PATH_IMAGE009
hexafluorophosphate (PyBOP), O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea
Figure 366040DEST_PATH_IMAGE009
a tetrafluoro borate (TBTU), O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea
Figure 29103DEST_PATH_IMAGE009
hexafluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyl-urea
Figure 492445DEST_PATH_IMAGE010
a tetrafluoro borate (TPTU), O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea
Figure 652818DEST_PATH_IMAGE009
hexafluorophosphate (HATU) or O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyl-urea
Figure 885216DEST_PATH_IMAGE009
a tetrafluoro borate (TCTU), optionally combine as I-hydroxybenzotriazole (HOBt) or N-hydroxy-succinamide (HOSu) with other auxiliary agent, and, as alkali, alkaline carbonate, for example sodium or potassium carbonate or supercarbonate, or organic bases is as trialkylamine, for example triethylamine, N-methylmorpholine, N-methyl piperidine or N, N-diisopropyl ethyl amine.Preferably, at N, there is the binding substances of the lower EDC of use and HOBt or TBTU in N-diisopropyl ethyl amine.
Condensation reaction (II)+(III) → (I) is generally between-20 DEG C to+60 DEG C, preferably between 0 DEG C to+40 DEG C, carries out.Reaction can be at barometric point, for example, under the pressure of raising or decompression (0.5 to 5 bar), carries out.This operation is generally carried out under barometric point.
The inert solvent of processing step (IV)+(V) → (I) is for example halohydrocarbon, as methylene dichloride, and trichloromethane, tetrachloromethane, trieline or chlorobenzene, ethers is as ether, and two
Figure 656863DEST_PATH_IMAGE002
alkane, tetrahydrofuran (THF), glycol dimethyl ether or diglyme, hydro carbons is as benzene, toluene, dimethylbenzene, hexane, hexanaphthene or petroleum fractions, or other solvent is as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, DMF, dimethyl sulfoxide (DMSO), N, N '-dimethylpropylene urea (DMPU), N-Methyl pyrrolidone (NMP) or pyridine.Similarly likely use the mixture of listed solvent.Preferably, use acetonitrile, acetone or dimethyl formamide.
As the alkali of processing step (IV)+(V) → (I), common inorganic or organic bases is suitable.These preferably include alkali metal hydroxide, for example lithium, sodium or potassium oxyhydroxide, basic metal or alkaline earth metal carbonate are as lithium, sodium, potassium, calcium or caesium carbonate, alkali metal alcoholate is as sodium or potassium methylate, sodium or potassium ethylate or sodium or potassium tert butoxide, alkalimetal hydride is as sodium or potassium hydride, aminate is as sodium amide, two (trimethyl silyl) aminates of lithium or potassium or di-isopropyl amination lithium, or organic amine is as triethylamine, N-methylmorpholine, N-methyl piperidine, N, N-diisopropylethylamine, pyridine, 1, 5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN), 1, 8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) or 1, 4-diazabicyclo [2.2.2] octane (DABCO ).Preferably, use salt of wormwood or cesium carbonate.
Here, this alkali is the amount with 1-5 mol, preferably use with the amount of 1-2.5 mol, taking the compound of the general formula (IV) of 1mol for basic.Reaction is generally at 0 DEG C to+100 DEG C, preferably in+20 DEG C to+80 DEG C temperature ranges, carries out.Reaction can be at barometric point, for example, under the pressure of raising or decompression (0.5 to 5 bar), carries out.This operation is generally carried out under barometric point.
The present invention includes following embodiment:
1.the compound of general formula (I)
Figure 669818DEST_PATH_IMAGE001
(I),
In formula
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen, (C 1-C 4) alkyl or trifluoromethyl,
R 6Bhydrogen or (C 1-C 4) alkyl,
R 7Ahydrogen, (C 1-C 4) alkyl or trifluoromethyl,
R 7Bhydrogen or (C 1-C 4) alkyl,
Q is CH or N,
R 1(C 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl or (C 3-C 7) cycloalkyl,
Wherein (C 1-C 6) alkyl, (C 2-C 6) alkenyl and (C 2-C 6) alkynyl can be selected from deuterium, halogen, cyano group, oxo, hydroxyl, trifluoromethyl, (C 3-C 7) cycloalkyl, (C 1-C 6) alkoxyl group, the 1-3 in trifluoromethoxy and phenyl substituting group replaces,
Wherein (C 3-C 7) cycloalkyl can be independently from each other (C 1-C 4) alkyl, oxo, hydroxyl, (C 1-C 4) in alkoxyl group and amino 1 or 2 substituting groups replace,
With
Wherein (C 1-C 6) alkoxyl group can be independently from each other amino, hydroxyl, (C 1-C 4) alkoxyl group, hydroxycarbonyl group and (C 1-C 4) 1 or 2 substituting group in alkoxy carbonyl replaces,
With
Wherein phenyl can be independently from each other halogen, cyano group, nitro, (C 1-C 4) alkyl, trifluoromethyl, hydroxyl, methylol, (C 1-C 4) alkoxyl group, trifluoromethoxy, (C 1-C 4) alkoxy methyl, hydroxycarbonyl group, (C 1-C 4) alkoxy carbonyl, aminocarboxyl, single (C 1-C 4) alkyl amino-carbonyl and two-(C 1-C 4) 1-3 substituting group in alkyl amino-carbonyl replace,
With
Wherein (C 3-C 7) cycloalkyl can be independently from each other fluorine, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, hydroxyl, 1 or 2 substituting group in amino and oxo replaces,
R 2benzothienyl, phenyl, thienyl or furyl,
Wherein benzothienyl, phenyl, thienyl and furyl can be independently from each other halogen, cyano group, nitro, (C 1-C 4) alkyl, trifluoromethyl, hydroxyl, (C 1-C 4) 1-3 substituting group in alkoxyl group and trifluoromethoxy replace,
R 3trifluoromethyl, hydroxyl, trifluoromethoxy, (C 1-C 4) alkoxyl group, (C 3-C 7) cycloalkyloxy, nitro, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21,-O-SO 2-NR 24r 25， – NR 26-SO 2-NR 27r 28huo – NR 30r 31,
Wherein
R 8hydrogen or (C 1-C 4) alkyl,
R 9hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 8and R 9together with the atom being connected to them, form 5 to 7-element heterocycles,
Wherein this 5-7 element heterocycle can be independently from each other fluorine, (C 1-C 4) 1 or 2 substituting group in alkyl and trifluoromethyl replaces,
R 10hydrogen or (C 1-C 4) alkyl,
R 11(C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 10and R 11together with the atom being connected to them, form 5 to 7-element heterocycles,
Wherein this 5-7 element heterocycle can be independently from each other fluorine, (C 1-C 4) 1 or 2 substituting group in alkyl and trifluoromethyl replaces,
R 12hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 13hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 12and R 13together with the nitrogen-atoms being keyed to them, form 4 to 7-element heterocycles,
Wherein this 4-7 element heterocycle can be independently from each other fluorine, oxo, hydroxyl, (C 1-C 4) 1 or 2 substituting group in alkyl and trifluoromethyl replaces,
R 14hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 15hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 14and R 15together with the nitrogen-atoms being keyed to them, form 4 to 7-element heterocycles,
Wherein this 4-7 element heterocycle can be independently from each other fluorine, oxo, hydroxyl, (C 1-C 4) 1 or 2 substituting group in alkyl and trifluoromethyl replaces,
R 16hydrogen or (C 1-C 4) alkyl,
R 17hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 18hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 5 to 7-element heterocycles,
Wherein this 5-7 element heterocycle can be independently from each other fluorine, trifluoromethyl and (C 1-C 4) 1 or 2 substituting group in alkyl replaces,
Or
R 17and R 18together with the nitrogen-atoms being keyed to them, form 4 to 7-element heterocycles,
Wherein this 4-7 element heterocycle can be independently from each other fluorine, oxo, hydroxyl, (C 1-C 4) 1 or 2 substituting group in alkyl and trifluoromethyl replaces,
R 19hydrogen or (C 1-C 4) alkyl,
R 20(C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 19and R 20together with the atom being connected to them, form 5 to 7-element heterocycles,
Wherein this 5-7 element heterocycle can be independently from each other fluorine, (C 1-C 4) 1 or 2 substituting group in alkyl and trifluoromethyl replaces,
N is numeral 0,1 or 2,
R 21hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 24hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 25hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 24and R 25together with the nitrogen-atoms being keyed to them, form 4 to 7-element heterocycles,
Wherein this 4-7 element heterocycle can be independently from each other fluorine, oxo, hydroxyl, (C 1-C 4) 1 or 2 substituting group in alkyl and trifluoromethyl replaces,
R 26hydrogen or (C 1-C 4) alkyl,
R 27hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 28hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 26and R 27together with the nitrogen-atoms being keyed to them, form 5 to 7-element heterocycles,
Wherein this 5-7 element heterocycle can be independently from each other fluorine, trifluoromethyl and (C 1-C 4) 1 or 2 substituting group in alkyl replaces,
Or
R 27and R 28together with the nitrogen-atoms being keyed to them, form 4 to 7-element heterocycles,
Wherein this 4-7 element heterocycle can be independently from each other fluorine, oxo, hydroxyl and (C 1-C 4) 1 or 2 substituting group in alkyl replaces,
R 30hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
R 31(C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 30and R 31together with the nitrogen-atoms being keyed to them, form 4 to 7-element heterocycles,
Wherein this 4-7 element heterocycle can be independently from each other fluorine, oxo, hydroxyl, (C 1-C 4) 1 or 2 substituting group in alkyl and trifluoromethyl replaces,
R 4be phenyl, naphthyl or 5 is to 10-person's heteroaryl,
Wherein phenyl, naphthyl and 5 to 10 Yuans heteroaryls can be independently from each other halogen, cyano group, nitro, (C 1-C 4) alkyl, difluoromethyl, trifluoromethyl, hydroxyl, (C 1-C 4) alkoxyl group, the substituting group of the 1-3 in difluoro-methoxy and trifluoromethoxy replaces,
R 5hydrogen, deuterium, trifluoromethyl or (C 1-C 4) alkyl,
R 29hydrogen or (C 1-C 4) alkyl,
And the salt of this compound, solvate, and the solvate of this salt.
2.according to the general formula of embodiment 1 (I) compound, wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen, methyl or trifluoromethyl,
R 6Bhydrogen or methyl,
R 7Ahydrogen, methyl or trifluoromethyl,
R 7Bhydrogen or methyl,
Q is CH or N,
R 1(C 1-C 6) alkyl, (C 2-C 6) alkenyl or (C 3-C 6) cycloalkyl,
Wherein (C 1-C 6) alkyl and (C 2-C 6) alkenyl can be independently from each other fluorine, chlorine, cyano group, oxo, hydroxyl, trifluoromethyl, (C 3-C 6) cycloalkyl, (C 1-C 4) alkoxyl group, the substituting group of the 1-3 in trifluoromethoxy and phenyl replaces,
Wherein (C 3-C 6) cycloalkyl can be independently from each other methyl, ethyl, oxo, hydroxyl, methoxyl group, 1 or 2 substituting group in oxyethyl group and amino replaces,
With
Wherein phenyl can be selected from fluorine, chlorine, and cyano group, methyl, ethyl, trifluoromethyl, methoxyl group, oxyethyl group, trifluoromethoxy, methoxymethyl, ethoxyl methyl, hydroxycarbonyl group, methoxycarbonyl, the substituting group in ethoxy carbonyl and aminocarboxyl replaces,
With
Wherein (C 3-C 6) cycloalkyl can be independently from each other fluorine, methyl, ethyl, methoxyl group, oxyethyl group, hydroxyl, 1 or 2 substituting group in amino and oxo replaces,
R 2thionaphthene-2-base, phenyl or thienyl,
Wherein thionaphthene-2-base, phenyl and thienyl can be independently from each other fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxyl, methoxyl group, 1 or 2 substituting group in oxyethyl group and trifluoromethoxy replaces,
R 3trifluoromethyl, hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21,-O-SO 2-NR 24r 25huo – NR 26-SO 2-NR 27r 28-,
Wherein
R 8hydrogen or methyl,
R 9(C 1-C 4) alkyl,
Or
R 8and R 9together with the atom being connected to them, form 5 to 7-element heterocycles,
R 10hydrogen or methyl,
R 11(C 1-C 4) alkyl,
Or
R 10and R 11together with the atom being connected to them, form 5 to 7-element heterocycles,
R 12(C 1-C 4) alkyl,
R 13(C 1-C 4) alkyl,
R 14hydrogen or (C 1-C 4) alkyl,
R 15hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 14and R 15together with the nitrogen-atoms being keyed to them, form 4 to 7-element heterocycles,
R 16hydrogen or (C 1-C 4) alkyl,
R 17hydrogen or (C 1-C 4) alkyl,
R 18hydrogen, (C 1-C 4) alkyl or (C 3-C 7) cycloalkyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 5 to 7-element heterocycles,
R 19hydrogen or methyl,
R 20(C 1-C 4) alkyl,
Or
R 19and R 20together with the atom being connected to them, form 5 to 7-element heterocycles,
N is numeral 0,1 or 2,
R 21(C 1-C 4) alkyl,
R 24hydrogen or methyl,
R 25hydrogen or methyl,
R 26hydrogen or methyl,
R 27hydrogen or (C 1-C 4) alkyl,
R 28hydrogen or (C 1-C 4) alkyl,
Or
R 26and R 27together with the nitrogen-atoms being keyed to them, form 5 to 7-element heterocycles,
R 4phenyl,
Wherein phenyl can be independently from each other fluorine, chlorine, and cyano group, methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxyl, methoxyl group, oxyethyl group, the substituting group of the 1-3 in difluoro-methoxy and trifluoromethoxy replaces,
R 5hydrogen, deuterium, trifluoromethyl, methyl or ethyl,
R 29hydrogen or methyl,
And the salt of this compound, solvate, and the solvate of this salt.
3.according to general formula (I) compound of embodiment 1 or 2, wherein
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen or trifluoromethyl,
R 6Bhydrogen,
R 7Ahydrogen,
R 7Bhydrogen,
Q is N,
R 1(C 2-C 4) alkyl, (C 2-C 4) alkenyl or cyclopropyl,
Wherein (C 2-C 4) alkyl and (C 2-C 4) alkenyl can be independently from each other fluorine, oxo, 1 or 2 substituting group in hydroxyl and trifluoromethyl replaces,
R 2phenyl,
The substituting group that wherein phenyl can be selected from fluorine or chlorine replaces,
R 3trifluoromethyl, hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21or-NR 26-SO 2-NR 27r 28-,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 12methyl,
R 13methyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 2-oxo-imidazole alkane-1-base or 2-oxo tetrahydropyrimidine-1 (2H)-basic ring,
R 19hydrogen,
R 20methyl or ethyl,
Or
R 19and R 20together with the atom being connected to them, form 2-oxo-1,3-
Figure 552324DEST_PATH_IMAGE011
azoles alkane-3-base or 2-oxo-1,3-
Figure 904808DEST_PATH_IMAGE011
piperazine alkane-3-basic ring,
N is numeral 0 or 2,
R 21methyl,
R 26hydrogen,
R 27hydrogen,
R 28hydrogen,
R 4it is the group of following structural formula
Figure 660405DEST_PATH_IMAGE004
Wherein
# is be connected to-C (R 5) (AR 3) link position on N-,
R 22hydrogen, fluorine, chlorine, trifluoromethyl and methoxyl group,
R 23hydrogen, fluorine, chlorine, trifluoromethyl and methoxyl group,
Wherein radicals R 22and R 23in at least one is not hydrogen,
R 5hydrogen or methyl,
R 29hydrogen,
And the salt of this compound, solvate, and the solvate of this salt.
4.the method of preparation defined general formula (I) compound in embodiment 1 to 3, is characterised in that
The compound of [A] general formula (II)
Figure 98340DEST_PATH_IMAGE005
(II)，
Wherein Q, R 1and R 2separately with in embodiment 1-3, define identical,
In inert solvent, utilize the activation of carboxylic acid functional, be coupled on the compound of general formula (III)
(III)，
Wherein A, R 3, R 4, R 5and R 29separately with identical definition in embodiment 1-3,
Or
The compound of [B] general formula (IV)
Figure 53843DEST_PATH_IMAGE007
(IV)，
Wherein Q, R 1and R 2separately with in embodiment 1-3, define identical,
In inert solvent, under existing, alkali reacts with the compound of logical formula V
Figure 167293DEST_PATH_IMAGE008
(V)，
Wherein A, R 3, R 4, R 5and R 29separately with identical definition in embodiment 1-3,
With
X 1be leavings group, as halogen, methylsulfonic acid is followed or toluenesulphonic acids is followed,
Then general formula (I) compound that obtained is optionally used (i) solvent and/or (ii) alkali or the sour solvate that changes into them accordingly, the solvate of salt and/or this salt.
5.according to the compound of any one defined general formula (I) in embodiment 1 to 3, it treats and/or prevents for disease.
6.according to any one defined general formula (I) compound in embodiment 1-3, it is for acute and chronic cardiac insufficiency, heavy body and general capacity hyponatremia, chronic inter stitial hepatitis, ascites, in the method treating and/or preventing of the syndromes (SIADH) of oedema and not enough ADH secretions.
7.be used for acute and chronic cardiac insufficiency according to any one defined general formula (I) compound in embodiment 1-3, heavy body and general capacity hyponatremia, chronic inter stitial hepatitis, ascites, the purposes in the production of the medicine that treats and/or prevents use of the syndromes (SIADH) of oedema and not enough ADH secretions.
8.medicine, it is included in any one defined general formula (I) compound in embodiment 1 to 3, and combines with vehicle suitable on inertia, nontoxic, pharmacology.
9.medicine, it comprises defined general formula (I) compound in any one in embodiment 1-3 combining with one or more other activeconstituentss, this other activeconstituents is selected from hydragog(ue), Angiotensin AII antagonist, ACE inhibitor, beta-blockers, mineralocorticoid receptor antagonist, organic nitrate, NO is to body and have the material that strengthens convergent force activity.
10.8 or 9 medicine as requested, it is for acute and chronic cardiac insufficiency, heavy body and general capacity hyponatremia, chronic inter stitial hepatitis, ascites, syndromes (SIADH) that oedema and enough ADH secrete treats and/or prevents.
11.use significant quantity in embodiment 1-3 in any one at least one compound of defined general formula (I) or significant quantity in embodiment 8-10 in any one defined medicine treat and/or prevent the acute and chronic cardiac insufficiency in human body and animal body, heavy body and general capacity hyponatremia, chronic inter stitial hepatitis, ascites, the method for the syndromes (SIADH) of oedema and not enough ADH secretions.
The preparation of the compounds of this invention can illustrate by following building-up reactions route:
reaction scheme 1
Figure 905573DEST_PATH_IMAGE012
Additionally, wherein A is-CH 2-or-CH 2-CH 2-general formula (I) compound also can by inert solvent under suitable reductive agent exists by the also preparation originally of the compound of general formula (XV),
Figure 129881DEST_PATH_IMAGE013
(XV),
Wherein Q, R 1, R 2, R 4, R 5and R 29separately as defined above,
With
T 1hydrogen or (C 1-C 4)-alkyl,
Obtain the compound of general formula (I-A):
Figure 519274DEST_PATH_IMAGE014
(I-A),
Wherein Q, R 1, R 2, R 4, R 5and R 29separately as defined above,
And, optionally, according to the known reaction of person of ordinary skill in the field and method; for example nucleophilic and electrophilic substitution, oxidation, reduction; hydrogenation, the linked reaction of transition metal-catalysis, cancellation; alkylation, amination, esterification; ester division, etherificate, ether division; with the introducing of temporary protection group with remove, allow further modification of compound (I-A).
Here, the suitable inert solvents of processing step (XV) → (I-A) is alcohols, as methyl alcohol, and ethanol, n-propyl alcohol or Virahol, or ethers is as ether, and two
Figure 538046DEST_PATH_IMAGE015
alkane, tetrahydrofuran (THF), glycol dimethyl ether, glycol dimethyl ether or diglyme, or halohydrocarbon is as methylene dichloride, trichloromethane, and tetracol phenixin or 1,2-ethylene dichloride, or other solvent is as dimethyl formamide.Equally likely use the mixture of listed solvent.Preferably use glycol dimethyl ether and tetrahydrofuran (THF).
The suitable reductive agent of processing step (XV) → (I-A) comprises hydroborate, for example sodium borohydride, sodium triacetoxy borohydride, lithium borohydride or sodium cyanoborohydride, aluminum hydride, for example lithium aluminum hydride, two (2-methoxy ethoxy) sodium aluminum hydrides or diisobutyl alanate, diborane or borine-tetrahydrofuran (THF) title complex.
Reaction (XV) → (I-A) is generally at 0 DEG C to+60 DEG C, preferably in the temperature range of 0 DEG C to+40 DEG C, carries out.
The compound of general formula (II) can obtain N by the alkylated reaction of the alkali induction of general formula (IV) compound 2-the compound (VII) that replaces and be hydrolyzed (referring to reaction scheme 2) by follow-up ester and obtain:
reaction scheme 2
Figure 950572DEST_PATH_IMAGE016
Wherein Q be general formula (VII) compound of N also can be in addition from N-(alkoxy carbonyl) the aryl sulphamide of known in the literature general formula (IX) [referring to, for example, M. Arnswald, W.P. Neumann, j. Org. Chem. 58(25), 7022-7028 (1993); E.P. Papadopoulos, j. Org. Chem. 41(6), 962-965 (1976)] preparation, this by between general formula (IX) compound and the diazanyl ester of general formula (VIII) react and subsequent alkylation on the N-4 position of triazolone (X) realizes (reaction scheme 3):
reaction scheme 3
Wherein Q is that general formula (IV) compound of N can be initial from the carboxylic hydrazides of general formula (XI), by between itself and the isocyanic ester of general formula (XII) or the carboxylamine nitrophenyl ester of general formula (XIII) react and the follow-up alkali induction cyclic action of intermediate hydrazine carboxylic acid amides (XIV) is prepared (reaction scheme 4):
reaction scheme 4
Wherein R 1corresponding to substituting group CH 2cH (OH) CF 3compound, at first according to reaction scheme 4, from isocyano alkyl acetate (XIIa) and (XI), react, obtain (XIVa).Follow-up alkaline cyclic action obtains triazolone (IVa).CF 3the introducing of group by (IVa) with trifluoroacetic anhydride (TFAA) reacting in pyridine realize.The ketone (IVb) obtaining can be converted to by reduction (IVc) (reaction scheme 5):
reaction scheme 5
Figure 490772DEST_PATH_IMAGE019
Wherein Q be CH general formula (II) compound can by between the alpha-amino group ketone of general formula (XVI) and the isocyanic ester of general formula (XVII) react and follow-up ester is hydrolyzed to obtain (reaction scheme 6).The compound of general formula (XVI) itself can, according to known in the literature mode, synthesize (reaction scheme 7) from the α-bromoketone of general formula (XVIII) and the amino ester of general formula (XIX):
reaction scheme 6
Figure 125016DEST_PATH_IMAGE020
reaction scheme 7
Figure 501246DEST_PATH_IMAGE021
General formula (III), (V), (VI), (VIII), (IX), (XI), (XII), (XIIa), (XIII), (XVII), compound (XIX) and (XX) obtains by the multiple commercial sources of known in the literature separately, or can be according to preparing similarly with known in the literature method, or according to the method preparation of describing in the experimental section of this specification sheets.
Other compound of the present invention also can, if necessary, initial from general formula (I) compound obtaining according to aforesaid method, by each substituting group (especially at R 1and R 3those that enumerate under name) the preparation that is converted of functional group.These conversions are to carry out according to the known ordinary method of person of ordinary skill in the field, and comprise, for example; some reactions like this, as nucleophilic and electrophilic substitution, oxidation; reduction, hydrogenation, the linked reaction of transition metal-catalysis; cancellation, alkylation, amination; esterification, ester division, etherificate; ether division, the introducing of the especially formation of carboxylic acid amides, and temporary protection group and removing.
The present invention further comprises the compound of general formula (III):
(III),
In formula
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen or trifluoromethyl,
R 6Bhydrogen,
R 7Ahydrogen,
R 7Bhydrogen,
Q is N,
R 3hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21or-NR 26-SO 2-NR 27r 28-,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 12methyl,
R 13methyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 2-oxo-imidazole alkane-1-base or 2-oxo tetrahydropyrimidine-1 (2H)-basic ring,
R 19hydrogen,
R 20methyl or ethyl,
Or
R 19and R 20together with the atom being connected to them, form 2-oxo-1,3- azoles alkane-3-base or 2-oxo-1,3-
Figure 612924DEST_PATH_IMAGE002
piperazine alkane-3-basic ring,
N is numeral 0 or 2,
R 21methyl,
R 26hydrogen,
R 27hydrogen,
R 28hydrogen,
R 4it is the group of following structural formula
Figure 982726DEST_PATH_IMAGE004
In formula
# is be connected to-C (R 5) (AR 3) link position on N-,
R 22hydrogen, fluorine, chlorine and trifluoromethyl,
R 23hydrogen, fluorine, chlorine and trifluoromethyl,
Wherein this radicals R 22and R 23in at least one be not hydrogen,
R 5hydrogen or methyl,
R 29hydrogen.
The present invention further comprises the compound of logical formula V:
Figure 138901DEST_PATH_IMAGE008
(V),
In formula
A Shi – C (R 6Ar 6B)-* Huo – C (R 6Ar 6B)-C (R 7Ar 7B)-*,
Wherein
* be to be connected to R 3on link position,
R 6Ahydrogen or trifluoromethyl,
R 6Bhydrogen,
R 7Ahydrogen,
R 7Bhydrogen,
Q is N,
R 3hydroxyl, amino ,-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21or-NR 26-SO 2-NR 27r 28-,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 12methyl,
R 13methyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 2-oxo-imidazole alkane-1-base or 2-oxo tetrahydropyrimidine-1 (2H)-basic ring,
R 19hydrogen,
R 20methyl or ethyl,
Or
R 19and R 20together with the atom being connected to them, form 2-oxo-1,3-
Figure 749005DEST_PATH_IMAGE002
azoles alkane-3-base or 2-oxo-1,3-
Figure 357841DEST_PATH_IMAGE002
piperazine alkane-3-basic ring,
N is numeral 0 or 2,
R 21methyl,
R 26hydrogen,
R 27hydrogen,
R 28hydrogen,
R 4it is the group of following structural formula
Figure 328071DEST_PATH_IMAGE004
Wherein
# is be connected to-C (R 5) (AR 3) link position on N-,
R 22hydrogen, fluorine, chlorine and trifluoromethyl,
R 23hydrogen, fluorine, chlorine and trifluoromethyl,
Wherein this radicals R 22and R 23in at least one be not hydrogen,
R 5hydrogen or methyl,
R 29hydrogen.
The present invention further comprises following compounds:
Figure 338752DEST_PATH_IMAGE022
5-(4-chloro-phenyl-)-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-2,4-dihydro-3H-1,2,4-triazole-3-ketone.
Compound according to the present invention has valuable pharmacology performance and can be used in preventing and/or treating of in human body and animal body various diseases and disease induction symptom.
Compound according to the present invention is the two V1a/V2 receptor antagonists of effective as selective, and it suppresses antidiuretic hormone activity in vitro and in vivo.
Compound according to the present invention is particularly suitable for preventing and/or treating of cardiovascular disorder.In this respect, the following target that can for example and preferably be mentioned as is indicated: acute and chronic cardiac insufficiency, arterial hypertension, coronary heart disease, stablize and unstable angina pectoris, myocardial ischaemia, myocardial infarction, shock, arteriosclerosis, atrium and ventricle arrhythmia, temporary transient and local asphyxia is fallen ill, apoplexy, struvite cardiovascular disorder, periphery and cardiovascular disease, peripheral circulation illness, the pulmonary hypertension of artery, the spasm of coronary artery and peripheral arterial, thrombosis, thromboembolic disorders, oedema forms for example pulmonary edema, cerebral edema, renal edema or cardiac insufficiency-relevant oedema, and restenosis, for example, at thrombolytic treatment, through skin-transluminal angioplasty (PTA), through the coronary angioplasty (PTCA) in chamber, restenosis after heart transplantation and bypass art.
In the sense of the present invention, term cardiac insufficiency also comprises more specific or relevant disease form, as right heart insufficiency, left heart insufficiency, total functional defect, local asphyxia myocardosis, swelling property myocardosis, congenital ventricle defect, heart valve defect, there is the cardiac insufficiency of heart valve defect, mitral stenosis, mitral valve insufficiency, aortic stenosis, aortic valve insufficiency, tricuspid stenosis, tricuspidal valve insufficiency, pulmonary stenosis, pulmonary valve insufficiency, the heart valve defect of combination, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, virus myocarditis, diabetogenous cardiac insufficiency, the myocardosis of alcoholism, heart storage disease, diastolic cardiac insufficiency and systaltic cardiac insufficiency.
In addition, compound according to the present invention is suitable as diuretic(s), for edema disease and ionogen illness, and the especially treatment of heavy body hyponatremia and normal capacity hyponatremia.
Also be suitable for the preventing and/or treating of syndromes (antidiuretic hormone secretion abnormal syndrome, SIADH) of polycystic kidney disease (PCKD) and enough ADH secretions according to compound of the present invention.
In addition, compound according to the present invention can be used in liver cirrhosis, ascites, diabetes and diabetogenous complication, for example neuropathy and ephrosis, the preventing and/or treating of acute and chronic renal failure and chronic renal insufficiency.
In addition, compound according to the present invention is suitable for center nervous disorders as anxiety illness and dysthymia disorders, glaucoma and cancer, especially preventing and/or treating of lung tumors.
In addition, compound according to the present invention can be used in diseases associated with inflammation, asthma disease, chronic-obstructive respiratory tract disease (COPD), antalgesic, prostatomegaly, incontinence, urocystitis, hyperactive bladder disease, for example pheochromocytoma of kidney disease and anemogenous lumbago, domestic disease is Crohn ' s disease and diarrhoea such as, or such as dysmenorrhoea of menoxenia, or the preventing and/or treating of endometriosis.
Additional object of the present invention is the purposes that treat and/or prevent of compound according to the present invention for disease, especially above-mentioned disease.
A further object of the present invention is that the compounds of this invention is for acute and chronic cardiac insufficiency, heavy body and normal capacity hyponatremia, liver cirrhosis, ascites, oedema, with the purposes in the method treating and/or preventing of the syndromes (antidiuretic hormone secretion abnormal syndrome, SIADH) of inadequate ADH secretion.
Additional object of the present invention is the purposes of compound according to the present invention for the production of the medicine treating and/or preventing for disease, especially above-mentioned disease.
Additional object of the present invention is to utilize at least one the compounds of this invention of significant quantity, for the method treating and/or preventing of disease, especially above-mentioned disease.
According to the compound of the present invention use that can use separately or if necessary combine with other active substance.Additional object of the present invention is the compounds of this invention that contains at least one and the medicine of one or more other active substances, is particularly useful for treating and/or preventing of above-mentioned disease.As the active substance of the use that combines that is suitable for this object, for example and preferably mention following material:
Organic nitrate and NO be to body, for example sodium nitroprusside, nitroglycerine, isosorbide 5-mono-nitrate, sorbitrate, molsidomine or SIN-1, and the NO sucking;
Diuretic(s), especially ring-type diuretic(s) and thiazides and thiazine shape diuretic(s);
Positive inotropic activity compound, for example cardiac glycoside (digoxin), and beta-adrenergic and dopaminergic agonist, as isoproterenol, suprarenin, norepinephrine, Dopamine HCL and dobutamine;
Suppress the compound of the degraded of cyclic guanine monophosphate (cGMP) (cGMP) and/or 3'5'-AMP (cAMP), the inhibitor of for example phosphodiesterase (PDE) 1,2,3,4 and/or 5, especially PDE 5 inhibitor are as vigour (sildenafil), Ai Lida (vardenafil) and sharp scholar (tadalafil), and PDE 3 inhibitor are as amrinone and Win-47203;
Natriuretic peptide, for example " atrial natriuretic peptide " (ANP, anaritide), " B-type natriuretic peptide " or " brain natriuretic factor(peptide) " (BNP, nesiritide), " C type natriuretic peptide " (CNP) and kidney source property natriuretic peptide (urodilatin);
Calcium sensitizer, for example, with preferred Simdax (levosimendan);
The NO-of guanylate cyclase and the activator of blood-dependent/non-dependent, be especially described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, the compound in WO 02/070462 and WO 02/070510;
But the NO-dependent/non-dependent blood-dependent stimulant of guanylate cyclase, especially for example guanylate cyclase agonist (riociguat) and be described in WO 00/06568, WO 00/06569, the compound in WO 02/42301 and WO 03/095451;
The inhibitor of Human neutrophil elastase (HNE), for example Sivelestat sodium tetrahydrate (sivelestat) or DX-890 (reltran);
The compound of Inhibitory signal transductory cascade, for example tyrosine kinase inhibitor, especially Xarelto (sorafenib), imatinib (imatinib), Gefitinib (gefitinib) and erlotinib (erlotinib);
Affect the compound of the energy metabolism of heart, for example, with preferred etomoxir (etomoxir), dichloroacetate (dichloracetate), ranolazine (ranolazine) or trimetazine;
There is the medicine of anti-thrombosis function, for example, with preferred platelet aggregation inhibitor, anti-coagulant or fibrinolytic (profibrinolytic) material;
The active substance reducing blood pressure, for example, with preferred calcium antagonist, Angiotensin AII antagonist, ACE inhibitor, anticatalyst (vasopeptidase) inhibitor, the inhibitor of neutral endopeptidase, endothelin antagonists, blood vessel tension peptide protoenzyme inhibitor, alpha receptor blocking agent, beta-blockers, mineralocorticoid receptor antagonist and rho-kinase inhibitor; And/or
Improve lipometabolic active substance, for example and preferably thryoid receptor agonist, for example and preferably HMG-CoA reductase enzyme or squalene synthetic inhibitor of cholesterol synthesis inhibitor, ACAT inhibitor, CETP inhibitor, MTP inhibitor, PPAR-α, PPAR-γ and/or PPAR-delta agonists, cholesterol absorption inhibitor, lipase inhibitor, polymkeric substance gallic acid sorbent material, gallic acid cell reabsorption inhibitor and lipoprotein (a) antagonist.
In a preferred embodiment of the invention, the compound according to the present invention administration (Combined Preparation) that combines with diuretic(s) class, for example and preferably Furosemide, bumetanide, torsemid, Hydrex, chlorothiazide, hydrochlorothiazide, Hydroflumethiazide, Methyclothiazide, many thiazines, trichlormethiazide, chlorine piperazine ketone, indapamide, methaqualone, chinethazone, acetazolamide, daranide, methazolamide, glycerine, isosorbide, mannitol, guanamprazine or triamterene.
The medicine with anti-thrombosis function is understood to preferably refer to be selected from the compound in platelet aggregation inhibitor, anti-coagulant or fibrinolytic (profibrinolytic) material.
In a preferred embodiment of the invention, the compound according to the present invention administration that combines with platelet aggregation inhibitor, for example and preferably Asprin, clopidogrel, ticlopidine or Dipyridamole.
In a preferred embodiment of the invention, according to compound of the present invention and thrombin inhibitors, for example, with preferred ximelagatran (ximelagatran), Melagatran (melagatran), Bivalirudin (bivalirudin) or gram match (clexane), Combined Preparation.
In a preferred embodiment of the invention, according to compound of the present invention and GPIIb/IIIa antagonist, for example, with preferred Tirofiban (tirofiban) or ReoPro (abciximab), Combined Preparation.
In a preferred embodiment of the invention, according to compound of the present invention and factor Xa inhibitor Combined Preparation, for example, with preferred rivaroxaban (rivaroxaban) (BAY 59-7939), DU-176b, Eliquis (apixaban), otamixaban (otamixaban), the non-husky class in ground (fidexaban), razaxaban (razaxaban), fondaparin (fondaparinux), Ai Zhuo heparin (idraparinux), PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
In a preferred embodiment of the invention, according to compound of the present invention and heparin or lower molecular weight (LMW) heparin derivatives Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and vitamin K antagon-and preferred tonka bean camphor-Combined Preparation.
Blood pressure drop agent is understood to preferably to refer to be selected from following compound in these: calcium antagonist, Angiotensin AII antagonist, ACE inhibitor, vasoactive peptidase inhibitors, the inhibitor of neutral endopeptidase, endothelin antagonists, blood vessel tension peptide protoenzyme inhibitor, alpha receptor blocking agent, beta-blockers, mineralocorticoid receptor antagonist, rho-kinase inhibitor and diuretic(s).
In a preferred embodiment of the invention, for example, according to compound of the present invention and calcium antagonist-and preferably nifedipine, amlodipine, Verapamilum or Odizem-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and Angiotensin AII antagonist-and preferred losartan (losartan), Candesartan (candesartan), valsartan (valsartan), telmisartan (telmisartan), or Embusartan (embusartan)-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and Angiotensin ACE antagonist-and preferred enalapril (enalapril), captopril (captopril), lisinopril (lisinopril), Ramipril (ramipril), delapril (delapril), fosinopril (fosinopril), quino Puli (quinopril), perindopril (perindopril) or group diindyl Puli (trandopril)-Combined Preparation.
In a preferred embodiment of the invention, according to compound of the present invention and vasoactive peptidase inhibitors or neutral endopeptidase (NEP) inhibitor Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and endothelin antagonists-and preferred bosentan (bosentan), darusentan (darusentan), BSF208075 (ambrisentan) or sitaxentan (sitaxsentan)-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and blood vessel tension peptide protoenzyme inhibitor-and preferred aliskiren (aliskiren), SPP-600 or SPP-800-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and α-1 receptor blocking agent-and preferred Prazosin-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and beta-blockers-and preferred Propranololum, Target, timolol, pindolol, alprenolol, Trasicor, penta butidrate, bupranol, trimepranol, nadolol, Corindolan, Suacron, sotolol, metoprolol, betaxolol, Celiprolol, bisoprolol, carteolol, esmolol, Trandate, Carvedilol, Adaprolol (adaprolol), Landiolol (landiolol), nebivolol (nebivolol), epanolol (epanolol) or bucindolol (bucindolol)-Combined Preparation.
In a preferred embodiment of the invention, according to compound of the present invention and mineralocorticoid receptor antagonist-for example and preferably Spironolactone, eplerenone (eplerenon), print sharp ketone (canrenon, canrenone) or print sharp sour potassium (potassium canrenoate, canrenoate potassium)-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and rho-kinase inhibitor-and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049-Combined Preparation.
Metabolism of fat-properties-correcting agent is understood to preferably to refer to be selected from following compound in these: CETP inhibitor, thryoid receptor agonist, cholesterol synthesis inhibitor is as HMG-CoA reductase enzyme or squalene synthetic inhibitor, ACAT inhibitor, MTP inhibitor, PPAR-α, PPAR-γ and/or PPAR-delta agonists, cholesterol absorption inhibitor, polymkeric substance gallic acid sorbent material, gallic acid cell reabsorption inhibitor, lipase inhibitor and lipoprotein (a) antagonist.
In a preferred embodiment of the invention, for example, according to compound of the present invention and CETP inhibitor-and preferably reach plug bent (dalcetrapib), BAY 60-5521, anacetrapib or CETP-vaccine (CETi-1)-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and thryoid receptor agonist-and preferred D-tetraiodothyronine (D-thyroxine), 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214)-Combined Preparation.
In a preferred embodiment of the invention, according to compound of the present invention be selected from statin class (statins)-for example and preferred lovastatin, Simvastatin, Pravastatin, fluorine cuts down Chinese violet, atorvastatin, superstatin or Pitavastatin-in HMG-CoA reductase inhibitor Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and squalene synthetic inhibitor-and preferably BMS-188494 or TAK-475-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and ACAT inhibitor-and preferred avasimibe (avasimibe), AC-233 (melinamide), handkerchief is for wheat cloth (pactimibe), eflucimibe or SMP-797-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and MTP inhibitor-and preferably implitapide, BMS-201038, R-103757 or JTT-130-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and PPAR-gamma agonist-and preferably U-721017E or rosiglitazone (rosiglitazone)-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and PPAR-delta agonists-and preferably GW-501516 or BAY 68-5042-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and cholesterol absorption inhibitor-and preferably ezetimibe (ezetimibe), tiqueside (tiqueside) or Pamaqueside (pamaqueside)-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and lipase inhibitor-and preferred orlistat (orlistat)-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and polymkeric substance gallic acid sorbent material-and preferably cholestyramine, cholestipol, colesolvam, cholestagel or colestimid-Combined Preparation.
In a preferred embodiment of the invention, for example, for example, according to compound of the present invention and gallic acid cell reabsorption inhibitor-and preferred ASBT (=IBAT) inhibitor, AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635-Combined Preparation.
In a preferred embodiment of the invention, for example, according to compound of the present invention and lipoprotein (a) antagonist-and preferably gemcabene calcium (CI-1027) or nicotinic acid-Combined Preparation.
Other object of the present invention is medicine, and the compounds of this invention that it contains at least one conventionally also contain together suitable additive on one or more inertia, nontoxic, pharmacology, and this medicine is for the purposes of above-mentioned purpose.
Can systematically and/or partly work according to compound of the present invention.For this purpose, they can be with suitable mode administration, for example oral, parenteral approach, and through lung, intranasal, through hypogloeeis, through tongue, through cheek, per rectum, through corium, transdermal, through conjunctiva or through ear approach or as implant or stent.
For these route of administration, can be with suitable form of medication administration according to compound of the present invention.
For oral administration, discharge those form of medication that work according to prior art of the compounds of this invention rapidly and/or with improved procedure, the compounds of this invention that it contains crystallization and/or amorphization and/or solubilized form, for example tablet is (without dressing or there is the tablet of dressing, for example have resistant to gastric juice or delayed dissolved or insoluble coating, the release of this coating control the compounds of this invention), the tablet of disintegration or film/thin slice rapidly in oral cavity, diaphragm/lyophilized products, capsule (for example hard or soft gelatin capsule), drageeing, particulate, pellet, powder, emulsion, suspension, aerosol or solution are suitable.
Administered parenterally can omit absorption step (for example intravenously, intra-arterial, intracardiac, in backbone or administration in waist) or comprise that absorption step (for example intramuscular, subcutaneous, intracutaneous, through skin or intraperitoneal administration) carries out.The suitable form of medication of administered parenterally comprises injection and the perfusion preparation of solution, suspension, emulsion, lyophilized powder or sterilized powder form.
For other route of administration, for example, suck preparaton (comprising powder inhalator and sprinker), nasal drop, solution or sprays; Through the tablet of tongue, hypogloeeis or cheek administration, tablet, film/disk or capsule, suppository, the preparation of oral or ophthalmic administration, vaginal capsule agent, aqeous suspension (washing lotion, the mixture that can vibrate), lipophilicity suspension, ointment, missible oil, percutaneous absorption type (for example patch), emulsion, slurry, foaming agent, face powder, implant or stent are suitable.
Oral or administered parenterally, especially oral and intravenous administration, is preferred.
Can change into described form of medication according to compound of the present invention.This can be according to known method itself, by mixing to carry out with additive suitable on inertia, nontoxic, pharmacology.These additives comprise carrier (for example Microcrystalline Cellulose, lactose, mannitol), solvent (for example liquid macrogol), emulsifying agent and dispersion agent or wetting agent (for example sodium lauryl sulphate, polyoxy sorbitan oleic acid ester (polyoxysorbitan oleate)), binding agent (for example polyvinylpyrrolidone), synthesize and natural polymer (for example white protein), stablizer (for example antioxidant as, as xitix), colorant (for example mineral dye, as ferriferous oxide) and correctives or smell modifying agent.
Generally, in order to realize effective result in administered parenterally, have been found that and advantageously use about 0.001-10 mg/kg, the dosage of preferred about 0.01-1 mg/kg body weight.In oral, this dosage is about 0.01-100 mg/kg, preferred about 0.01-20 mg/kg and quite especially preferably 0.1-10 mg/kg body weight.
However, sometimes needing has deviation with this amount, depends on body weight, route of administration, individual response, the character of preparation and the time of administration or interval to active substance.Therefore use in some cases lower than above-mentioned minimum quantity and be enough to tackle, and the described upper limit must be exceeded in other cases.If while carrying out administration with larger amount, these need to be divided into administration several times in a day.
Following concrete instance is used for illustrating the present invention.The present invention is not limited to these embodiment.
Except as otherwise noted, otherwise, be weight percent at the per-cent described in following test and embodiment, part be weight part, and solvent ratio, dilution ratio and about the concentration information of liquid/liquid solution separately based on volume.
A. embodiment
abbreviation:
BOC tert-butoxycarbonyl
CI chemi-ionization (in MS)
DCI direct chemical ionization (in MS)
DME 1,2-glycol dimethyl ether
DMF dimethyl formamide
DMSO dimethyl sulfoxide (DMSO)
EDC N '-(3-dimethylaminopropyl)-N-ethyl-carbodiimide hydrochloride
Eq. equivalent
ESI electrospray ionization (in MS)
GC/MS vapor-phase chromatography-coupling mass spectrometry
Sat. saturated
H hour
HOBt 1-hydroxyl-1 h-benzotriazole hydrate
HPLC high pressure, high performance liquid chromatography
HV high vacuum
LC/MS liquid phase chromatography-coupling mass spectrometry
LDA di-isopropyl amination lithium
LiHMDS hexamethyldisilazane lithium
Min (s) minute
MS mass spectrometry
MTBE methyl tertiary butyl ether
NMR nuclear magnetic resonance spectroscopy(NMR spectroscopy)
Rac racemize/racemoid
R fretention factors (in tlc on silica gel)
RT room temperature
R tretention time (in HPLC)
THF tetrahydrofuran (THF)
TMOF orthoformic acid trimethylammonium ester
UV ultraviolet spectroscopy
V/v (solution) volume-volume ratio.
lC/MS, HPLC and GC/MS method:
method 1:mS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance 2795; Chromatographic column: Phenomenex Synergi 2.5 μ MAX-RP 100A Mercury, 20 mm × 4 mm; The 50% concentration formic acid of water+0.5 ml of mobile phase A:1 l, the 50% concentration formic acid of acetonitrile+0.5 ml of eluent B:1 l; Gradient: minute 5%A → 4.0, minute 90%A → 3.0,0.0 minute 90%A → 0.1 minute 5%A → 4.01 minute 90%A; Flow rate: 2 ml/min; Baking oven: 50 DEG C; UV detects: 210 nm.
method 2:mS instrument type: Waters (Micromass) Quattro Micro; HPLC instrument type: Agilent 1100 series; Chromatographic column: Thermo Hypersil GOLD 3 μ 20 x 4 mm; Eluent A:1 l water+0.5 ml 50% concentration formic acid; Eluent B:1 l acetonitrile+0.5 ml 50% concentration formic acid; Gradient: minute 10% A → 4.01, minute 10% A → 4.0,0.0 minute 100% A → 3.0 minute 100% A (flow 2.5 ml) → 5.00 minutes 100% A; Baking oven: 50 DEG C; Flow rate: 2 mL/min; UV detects: 210 nm.
method 3:instrument: with the Micromass Quattro Premier of Waters UPLC Acquity; Chromatographic column: Thermo Hypersil GOLD 1.9 μ, 50 × 1 mm; The 50% concentration formic acid of water+0.5 ml of eluent A:1 l, the 50% concentration formic acid of acetonitrile+0.5 ml of eluent B:1 l; Gradient: minute 10%A → 2.2, minute 90%A → 1.5,0.0 minute 90%A → 0.1 minute 10%A; Baking oven: 50 DEG C; Flow rate: 0.33 ml/min; UV detects: 210 nm.
method 4:instrument: Waters ACQUITY SQD UPLC System; Chromatographic column: Waters Acquity UPLC HSS T3 1.8 μ 50 × 1 mm; The 99% concentration formic acid of water+0.25 ml of eluent A:1 l, the 99% concentration formic acid of acetonitrile+0.25 ml of eluent B:1 l; Gradient: 0.0 minute 90%A → 1.2 minute 5%A → 2.0 minute 5%A; Baking oven: 50 DEG C; Flow rate: 0.40 ml/min; UV detects: 210-400 nm.
method 5;instrument: Waters ACQUITY SQD UPLC System; Chromatographic column: Waters Acquity UPLC HSS T3 1.8 μ 50 × 1 mm; The 99% concentration formic acid of water+0.25 ml of eluent A:1 l, the 99% concentration formic acid of acetonitrile+0.25 ml of eluent B:1 l; Gradient: 0.0 minute 90%A → 1.2 minute 5%A → 2.0 minute 5%A; Baking oven: 50 DEG C; Flow rate: 0.40 ml/min; UV detects: 210-400 nm.
method 6:mS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 series; UV DAD; Chromatographic column: Phenomenex Gemini 3 μ, 30 mm × 3.0 mm; The 50% concentration formic acid of water+0.5 ml of eluent A:1 l, the 50% concentration formic acid of acetonitrile+0.5 ml of eluent B:1 l; Gradient: minute 5%A → 4.5, minute 30%A → 3.0,0.0 minute 90%A → 2.5 minute 5%A; Flow rate: 0.0 minute 1 ml/min, 2.5 minutes/3.0 minutes/4.5 minutes 2 ml/min; Baking oven: 50 DEG C; UV detects: 210 nm.
method 7:mS instrument type: Waters ZQ; HPLC instrument type: Agilent 1100 series; UV DAD; Chromatographic column: Thermo Hypersil GOLD 3 μ 20 mm x 4 mm; Eluent A:1 l water+0.5 ml 50% concentration formic acid; Eluent B:1 l acetonitrile+0.5 ml 50% concentration formic acid; Gradient: minute 10% A → 4.1, minute 10% A → 4.0,0.0 minute 100% A → 3.0 minute 100% flow rate: 2.5 ml/min; Baking oven: 55 DEG C; Flow rate 2 ml/min; UV detects: 210 nm.
method 8 (the chirality property prepared HPLC):taking selective agent Poly-(N-methacryloyl-D-Leu-bicyclic methyl propyl acid amides) as the static silica gel phase of basic chirality; Chromatographic column: 670 mm x 40 mm, flow rate: 80 ml/min, temperature: 24 DEG C; UV detector 260 nm.Eluent: isohexane/ethyl acetate 30:70.
method 8a:eluent: isohexane/ethyl acetate 10:90 (v/v); Flow rate: 50 ml/min.
method 9 (chiral analysis HPLC):taking selective agent Poly-(N-methacryloyl-D-Leu-bicyclic methyl propyl acid amides) as the static silica gel phase of basic chirality; Chromatographic column: 250 mm x 4.6 mm, eluent ethyl acetate 100%, flow rate: 1 ml/min, temperature: 24 DEG C; UV detector 265 nm.
method 10 (preparation property HPLC):chromatographic column: Grom-Sil 120 ODS-4HE, 10 μ m, SNo. 3331,250 mm x 30 mm. eluent A:0.1% aqueous formic acids, eluent B: acetonitrile; Flow rate: 50 ml/min program: 0-3 minute: 10% B; 3-27 minute: gradient-95% B; 27-34 minute: 95% B; 34.01-38 minute: 10% B.
method 11 (the chirality property prepared HPLC):static phases Daicel Chiralcel OD-H, 5 μ m, chromatographic column: 250 mm × 20 mm; Temperature: RT; UV detects: 230 nm.Various eluents:
method 11a:eluent: isohexane/Virahol 70:30 (v/v); Flow rate: 20 ml/min
method 11b:eluent: isohexane/Virahol 50:50 (v/v); Flow rate: 18 ml/min
method 11c:eluent: isohexane/methanol/ethanol 70:15:15; (v/v/v); Flow rate: 20 ml/min
method 11d:eluent: isohexane/Virahol 75:25 (v/v); Flow rate: 15 ml/min
method 12 (chiral analysis HPLC):static phases Daicel Chiralcel OD-H, chromatographic column: 250 mm × 4 mm; Flow rate: 1 ml/min; Temperature: RT; UV detects: 230 nm.Various eluents:
method 12a:eluent: isohexane/Virahol 1:1 (v/v);
method 12b:eluent: isohexane/methanol/ethanol 70:15:15 (v/v/v)
method 12c:eluent: isohexane/Virahol 75:25 (v/v);
method 13 (the chirality property prepared HPLC):taking selective agent poly-(N-methacryloyl-D-Leu-bicyclic methyl propyl acid amides) as the static silica gel phase of basic chirality; Chromatographic column: 600 mm x 30 mm, eluent: step gradient ethyl acetate/methanol 1:1 (0-17 minute) → ethyl acetate (17.01 minutes-21 minutes) → ethyl acetate/methanol 1:1 (21.01 minutes-25 minutes); Flow rate: 80 ml/min, temperature: 24 DEG C; UV detector: 265 nm.
method 13a:identical with method 13, but eluent: 0-5.08 minute isohexane/ethyl acetate 10:90, then ethyl acetate 100%
method 13b:eluent: 100% ethyl acetate
method 14 (chiral analysis HPLC):identical with method 9, but flow rate: 2 ml/min.
method 15 (the chirality property prepared HPLC):taking selective agent Poly-(N-methacryloyl-ILE-3-amyl group acid amides) as the static silica gel phase of basic chirality; Chromatographic column: 430 mm x 40 mm, flow rate: 80 ml/min, temperature: 24 DEG C; UV detector: 260 nm.Various eluents:
method 15a:100% ethyl acetate
method 15b;isohexane/ethyl acetate 10:90
method 16 (chiral analysis HPLC):taking selective agent Poly-(N-methacryloyl-ILE-3-amyl group acid amides) as the static silica gel phase of basic chirality; Chromatographic column: 250 mm x 4.6 mm, eluent 100% ethyl acetate, flow rate: 2 ml/min, temperature: 24 DEG C; UV detector 265 nm.
method 17 (the chirality property prepared HPLC):taking selective agent Poly-(N-methacryloyl-L-Leu-(+)-3-pinane methyl nitrosourea) as the static silica gel phase of basic chirality; Chromatographic column: 600 mm x 30 mm, flow rate: 80 ml/min, temperature: 24 DEG C; UV detector 265 nm.Various eluents:
method 17a:isohexane/ethyl acetate 20:80
method 17b:isohexane/ethyl acetate 30:70
method 17c:isohexane/ethyl acetate 50:50
method 17d:100% ethyl acetate
method 17e:isohexane/ethyl acetate 40:60
method 17f:isohexane/ethyl acetate 10:90
method 18 (chiral analysis HPLC):taking selective agent poly-(N-methacryloyl-L-Leu-(+)-3-pinane methyl nitrosourea) as the static silica gel phase of basic chirality; Chromatographic column: 250 mm x 4.6 mm, temperature: 24 DEG C; UV detector 265 nm.
method 18a:eluent: isohexane/ethyl acetate 50:50, flow rate: 2 ml/min.
method 18b:eluent: 100% ethyl acetate, flow rate: 2 ml/min.
method 18c:eluent: 100% ethyl acetate, flow rate: 1 ml/min.
method 19 (preparation property HPLC):chromatographic column Grom-Sil 120 ODS-4HE 10 μ m, 250 mm x 30 mm; Eluent: A=water, B=acetonitrile; Gradient: 0.0 minute 10% B, 3 minutes 10% B, 30 minutes 95% B, 42 minutes 95% B, 42.01 minutes 10% B, 45 minutes 10% B; Flow rate: 50 ml/min; Column temperature: room temperature; UV detects: 210 nm.
method 20 (preparation property HPLC):chromatographic column: Reprosil C18,10 μ m, 250 mm x 30 mm; Eluent A:0.1% aqueous formic acid, eluent B: methyl alcohol; Flow rate: 50 ml/min.; Program: 0-4.25 minute: 90% A/10% B; 4.26-4.5 minute: gradient-60% B; 4.5-11.5 minute: gradient-80% B; 11.51-17 minute: gradient-100% B; 17.01-19.5 minute 100% B; 19.51-19.75 gradient-40% B; 19.76-20.51 minute: 60% A/40% B.
method 21 (the chirality property prepared HPLC):static phases Daicel Chiralpak AS-H, 5 μ m, chromatographic column: 250 mm × 20 mm; Temperature: RT; UV detects: 230 nm; Flow rate: 20 ml/min; Various eluents:
method 21a:eluent: isohexane/Virahol 65:35
method 21b:eluent: isohexane/Virahol 50:50; Flow rate 20 ml/min
method 22 (chiral analysis HPLC):static phases Daicel Chiralpak AD-H 5 μ m, chromatographic column: 250 mm × 4 mm; UV detects: 220 nm; Flow rate: 1 ml/min; Eluent: isohexane/Virahol 50:50.
method 23 (preparation property HPLC):chromatographic column: YMC ODS C18,10 μ m, 250 mm x 30 mm; Eluent A:0.1% aqueous formic acid, eluent B: methyl alcohol; Flow rate: 50 ml/min.; Program: 0-4.25 minute: 90% A/10% B; 4.26-4.5 minute: gradient-60% B; 4.5-11.5 minute: gradient-80% B; 11.51-17 minute gradient-100% B; 17.01-19.5 minute 100% B; 19.51-19.75 gradient-40% B; 19.76-20.51 minute: 60% A/40% B.
method 24 (the chirality property prepared HPLC):taking selective agent Poly-(N-methacryloyl-L-Leu-tert-butylamides) as the static silica gel phase of basic chirality, on irregular (classification) vinyl silicagel column; 250 mm x 20 mm, flow rate: 45 ml/min, temperature: RT; UV detector 260 nm.Various eluents:
method 24a:isohexane/ethyl acetate 10:90
method 24b:isohexane/ethyl acetate 20:80
method 25 (chiral analysis HPLC):taking selective agent Poly-(N-methacryloyl-L-Leu-tert-butylamides) as the static silica gel phase of basic chirality, on irregular (classification) vinyl silicagel column; 250 mm x 4 mm, flow rate: 1.5 ml/min, temperature: RT; UV detector 260 nm.Various eluents:
method 25a:isohexane/ethyl acetate 20:80
method 25b:isohexane/ethyl acetate 30:70
method 26 (the chirality property prepared HPLC):static phases Daicel Chiralpak AD-H, 5 μ m, chromatographic column: 250 mm × 20 mm; Temperature: RT; UV detects: 230 nm; Flow rate: 20 ml/min; Various eluents:
method 26a:isohexane/Virahol 65:35 (v/v)
method 26b:isohexane/Virahol 80:20 (v/v)
method 26c:isohexane/Virahol 50:50 (v/v)
method 26d:isohexane/ethanol 65:35 (v/v)
method 26e:isohexane/ethanol 50:50 (v/v)
method 27 (chiral analysis HPLC):static phases Daicel Chiralpak AD-H, 5 μ m, chromatographic column: 250 mm x 4 mm; Temperature: 30 DEG C; UV detects: 230 nm; Flow rate: 1 ml/min; Various eluents:
method 27a:isohexane/Virahol 50:50 (v/v)
method 27b:isohexane/Virahol 60:40 (v/v)
method 27c:isohexane/Virahol/20% trifluoroacetic acid 75:24:1 (v/v/v)
method 27d:isohexane/ethanol 50:50 (v/v)
method 28 (the chirality property prepared HPLC):taking selective agent Poly-(N-methacryloyl-L-Leu-(+)-3-pinane methyl nitrosourea) as the static silica gel phase of basic chirality; Chromatographic column: 600 mm x 40 mm, temperature: RT; UV detector 265 nm; Eluent: isohexane/Virahol 80:20 (v/v); Flow rate: 50 ml/min.
method 29 (the chirality property prepared HPLC):taking selective agent Poly-(N-methacryloyl-D-Val-3-amyl group acid amides) as basic chirality static phases, on spherical sulfydryl silica gel; Chromatographic column: 250 mm x 20 mm, temperature: RT; UV detector 260 nm; Eluent: isohexane/Virahol 60:40 (v/v); Flow rate: 20 ml/min.
method 30 (the chirality property prepared HPLC):taking selective agent Poly-(N-methacryloyl-D-Val-3-amyl group acid amides) as basic chirality static phases, on spherical sulfydryl silica gel; Chromatographic column: 250 mm x 4 mm, temperature: RT; UV detector 260 nm; Eluent: isohexane/Virahol 60:40 (v/v); Flow rate: 1.5 ml/min.
method 31 (LC-MS):mS instrument type: Waters ZQ; HPLC instrument type: Agilent 1100 series; UV DAD; Chromatographic column: Thermo Hypersil GOLD 3 μ 20 mm x 4 mm; Eluent A:1 l water+0.5 ml 50% concentration formic acid; Eluent B:1 l acetonitrile+0.5 ml 50% concentration formic acid; Gradient: minute 10% A → 4.1, minute 10% A → 4.0,0.0 minute 100% A → 3.0 minute 100% flow rate: 2.5 ml/min; Baking oven: 55 DEG C; Flow rate 2 ml/min; UV detects: 210 nm.
method 32 (preparation property HPLC):chromatographic column: Reprosil C18,10 μ m, 250 mm x 40 mm; Eluent A:0.1% aqueous formic acid, eluent B: acetonitrile; Flow rate: 50 ml/min.; Program: 0-6 minute: 90% A/10% B; 6-40 minute: gradient-95% B; 40-53 minute: 5% A/95% B; 53.01-54 minute: gradient-10% B; 54.01-57 minute: 90% A/10% B.
method 33 (the chirality property prepared HPLC):taking selective agent poly-(N-methacryloyl-D-Leu-bicyclic methyl propyl acid amides) as basic chirality static phases, on spherical vinyl silica gel; Chromatographic column: 670 mm x 40 mm, flow rate: 80 ml/min, temperature: 24 DEG C; UV detector 265 nm; Eluent: 0-7.75 minute: 100% ethyl acetate; 7.76 minutes-12.00 minutes: 100% methyl alcohol; 12.01 minutes-16.9 minutes: 100% ethyl acetate.
method 34:chiral analysis HPLC under SFC (supercritical fluid chromatography) condition: taking selective agent poly-(N-methacryloyl-D-Leu-bicyclic methyl propyl acid amides) as basic chirality static phases, on spherical vinyl silica gel; Chromatographic column: 250 mm x 4.6 mm, temperature: 35 DEG C, eluent: CO 2/ methyl alcohol 67:33; Pressure: 120 bar, flow rate: 4 ml/min, UV detector 250 nm.
Initial compounds and intermediate:
Embodiment 1A
N-(2-[(4-chloro-phenyl-) and carbonyl] diazanyl } carbonyl) glycine ethyl ester
Figure 306708DEST_PATH_IMAGE023
The suspension that the 4-chlorobenzene hydrazides of 12.95 g (75.9 mmol) is formed in the dry THF of 50 ml is introduced at 50 DEG C, then drips the solution being formed by the 2-isocyano acetic acid ethyl ester of 10.0 g (77.5 mmol) and carry out blending in the dry THF of 100 ml.First form solution, then produce throw out.After interpolation finishes, mixture stirs 2 hours at 50 DEG C again, then at room temperature leaves standstill a night.Crystal is by filtering separation, with a small amount of ether washing, then dry in HV.This obtains the title compound of 21.43 g (theoretical value 89%).
LC/MS [method 1]: R t=1.13 min; M/z=300 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 10.29 (s, 1H), 8.21 (s, 1H), 7.91 (d, 2H), 7.57 (d, 2H), 6.88 (br.s, 1H), 4.09 (q, 2H), 3.77 (d, 2H), 1.19 (t, 3H)。
Embodiment 2A
[3-(4-chloro-phenyl-)-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl] acetic acid
Figure 215889DEST_PATH_IMAGE024
The compound of the embodiment 1A of 21.43 g (67.93 mmol) and the 3N aqueous sodium hydroxide solution blending of 91 ml are then heated a night under refluxing.After being cooled to room temperature, mixture is adjusted to 1 pH value by the slow interpolation of approximately 20% concentration hydrochloric acid.The solid by filtration of precipitation is separated, washes with water, then drying under reduced pressure at 60 DEG C.Output: 17.55 g (90% of theoretical value, approximately 88% purity).
LC/MS [method 1]: R t=0.94 min; M/z=254 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 13.25 (br.s, 1H), 12.09 (s, 1H), 7.65-7.56 (m, 4H), 4.45 (s, 2H)。
Embodiment 3A
5-(4-chloro-phenyl-)-4-(the fluoro-2-oxopropyl of 3,3,3-tri-)-2,4-dihydro-3H-1,2,4-triazole-3-ketone (or, hydrated form: 5-(4-chloro-phenyl-)-4-(3,3,3-tri-is fluoro-2,2-dihydroxypropyl)-2,4-dihydro-3H-1,2,4-triazole-3-ketone)
Figure 927493DEST_PATH_IMAGE025
The compound of the embodiment 2A of 5 g (16.36 mmol) is dissolved in the pyridine of 200 ml in argon gas, then with the trifluoroacetic anhydride (TFAA) blending of 17.18 g (81.8 mmol).Temperature is increased to approximately 35 DEG C.After 30 minutes, on rotatory evaporator, remove pyridine, the 0.5N hydrochloric acid dilution of 1.5 L for residue.Mixture is heated to 70 DEG C, then filters while hot.The a small amount of water washing of solid.Whole filtrate is extracted with ethyl acetate three times.The organic phase merging washes with water, then with saturated sodium bicarbonate aqueous solution washing, then with saturated sodium-chloride water solution washing, dry on sodium sulfate, then on rotatory evaporator, removes desolventizing.Residue is dry under HV.Output: the title compound of the hydrated form of 3.56 g (theoretical value 68%).
LC/MS [method 1]: R t=1.51 min; M/z=306 (M+H) +with 324 (M+H) +(ketone and hydrate)
1H NMR (DMSO-d 6, 400 MHz): δ = 12.44 (s, 1H), 7.72 (d, 2H), 7.68 (br.s, 2H), 7.61 (d, 2H), 3.98 (s, 2H)。
Embodiment 4A
5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2,4-dihydro-3H-1,2,4-triazole-3-ketone
Figure 792681DEST_PATH_IMAGE026
The compound of the embodiment 3A of 3.56 g (11 mmol) is dissolved in the methyl alcohol of 100 ml, then in the sodium borohydride blending (gas effusion) with ice-cooled lower and 3.75 g (99 mmol).After 1.5 hours, add at leisure the 1M hydrochloric acid of 200 ml.On rotatory evaporator, remove methyl alcohol, the water dilution of 500 ml for residue, is then extracted with ethyl acetate three times.The organic phase merging is washed with saturated sodium bicarbonate aqueous solution, then with saturated sodium-chloride water solution washing, dry on sodium sulfate, then on rotatory evaporator, removes desolventizing.Residue is dry under HV.This obtains the title compound of 3.04 g (theoretical value 90%).
LC/MS [method 2]: R t=1.80 min; M/z=308 (M+H) +.
1H NMR (DMSO-d 6, 400 MHz): δ = 12.11 (s, 1H), 7.75 (d, 2H), 7.62 (d, 2H), 6.85 (d, 1H), 4.34-4.23 (m, 1H), 3.92 (dd, 1H), 3.77 (dd, 1H)。
Embodiment 5A
[3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid methyl ester
Figure 993855DEST_PATH_IMAGE027
The compound of the embodiment 4A of 3.04 g (9.9 mmol) is dissolved in the acetonitrile of 100 ml, then with the methyl chloroacetate of 1.07 g (9.9 mmol), the potassiumiodide blending of the salt of wormwood of 2.73 g (19.8 mmol) and little spoon point.Reaction mixture heats 1 hour under refluxing, and is cooled to room temperature, then filters.Filtrate is removed volatile constituent on rotatory evaporator, and then residue is dry in HV.Output: the title compound of approximately 90% purity of 3.70 g (theoretical value 89%).
LC/MS [method 3]: R t=1.10 min; M/z=380 (M+H) +.
1H NMR (DMSO-d 6, 400 MHz): δ = 7.78 (d, 2H), 7.64 (d, 2H), 6.91 (d, 1H), 4.72 (s, 2H), 4.16-4.35 (m, 1H), 3.99 (dd, 1H), 3.84 (dd, 1H), 3.70 (s, 3H)。
Embodiment 5A racemic compound can be split as its enantiomer embodiment 6A and embodiment 7A by the preparation HPLC going up mutually in chirality, and they are early described in WO 2007/134862.
Chromatographic column: taking selective agent poly-(N-methacryloyl-ILE-3-amyl group acid amides) as basic chirality silica gel phase, 430 mm × 40 mm; Eluent: step gradient isohexane/ethyl acetate 1:1 → ethyl acetate → isohexane/ethyl acetate 1:1; Flow rate: 50 ml/min; Temperature: 24 DEG C; UV detects: 260 nm.
This racemic compound from the embodiment 5A of 3.6 g (be dissolved in the ethyl acetate of 27 ml and the isohexane of 27 ml and by chromatographic column and be separated into three parts), obtain the enantiomer 1 (it is wash-out first) (embodiment 6A) of 1.6 g, and the enantiomer 2 (it is wash-out subsequently) (embodiment 7A) of 1.6 g.
Embodiment 6A
3-(4-chloro-phenyl-)-5-oxo-4-[(2S) and-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetic acid methyl ester (enantiomer I)
Figure 577283DEST_PATH_IMAGE028
The enantiomer of wash-out first from the racemate resolution of embodiment 5A.
Rt=3.21 min [chromatographic column: taking selective agent poly-(N-methacryloyl-ILE-3-amyl group acid amides) as basic chirality silica gel phase, 250 mm × 4.6 mm; Eluent: isohexane/ethyl acetate 1:1; Flow rate: 1 ml/min; UV detects: 260 nm].
Embodiment 7A
3-(4-chloro-phenyl-)-5-oxo-4-[(2R) and-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetic acid methyl ester (enantiomer II)
Figure 92578DEST_PATH_IMAGE029
The enantiomer of last wash-out from the racemate resolution of embodiment 5A.
Rt=4.48 min [chromatographic column: taking selective agent poly-(N-methacryloyl-ILE-3-amyl group acid amides) as basic chirality silica gel phase, 250 mm × 4.6 mm; Eluent: isohexane/ethyl acetate 1:1; Flow rate: 1 ml/min; UV detects: 260 nm].
Embodiment 8A
3-(4-chloro-phenyl-)-5-oxo-4-[(2S) and-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetic acid
The ester of the enantiomer-pure of embodiment 6A (1.6 g, 4.21 mmol) is dissolved in the methyl alcohol of 77 ml, then with the 1M lithium hydroxide aqueous solution blending of 17 ml.Mixture at room temperature stirs 1 hour, then concentrated on rotatory evaporator.The water dilution of 100 ml for residue, then the pH value to 1-2 with 1N hcl acidifying.The product of precipitation is separated by filtering, and water and hexanaphthene washing, then blot in succession.After further dry in HV, obtain title compound (1.1 g, theoretical value 71%).
[α] d 20=+3.4 ° (methyl alcohol, c=0.37 g/100 ml)
LC/MS [method 1]: R t=1.51 min; M/z=366 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 3.84 (dd, 1H), 4.00 (dd, 1H), 4.25 (m, 1H), 4.58 (s, 2H), 6.91 (d, 1H), 7.63 (d, 2H), 7.78 (d, 2H), 13.20 (br. s, 1H)。
Embodiment 9A
3-(4-chloro-phenyl-)-5-oxo-4-[(2R) and-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetic acid
Figure 997398DEST_PATH_IMAGE031
According to the mode identical with embodiment 8A, obtain title compound from embodiment 7A.
[α] d 20=-4.6 ° (methyl alcohol, c=0.44 g/100 ml)
LC/MS [method 1]: R t=1.53 min; M/z=366 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 3.84 (dd, 1H), 4.00 (dd, 1H), 4.25 (m, 1H), 4.58 (s, 2H), 6.91 (d, 1H), 7.63 (d, 2H), 7.78 (d, 2H), 13.20 (br. s, 1H)。
Embodiment 10A
{ (phenyl sulfonyl) [3-(trifluoromethyl) phenyl] methyl } carboxylamine tertiary butyl ester
The benzene sulfinic acid sodium salt of the carboxylamine tertiary butyl ester of consumption 4.49 g (38.29 mmol) and 12.57 g (76.57 mmol) is incorporated in the methanol/water (1:2) of 110 ml, then in succession with the formic acid blending of 3-(trifluoromethyl) phenyl aldehyde and 2.87 ml (76.09 mmol) of 10 g (57.43 mmol).Mixture at room temperature stirs 30 hours.The product of precipitation is separated by filtering, and water and ether washing, then blot in succession.The further dry title compound that obtains 11.2 g (theoretical value 47%) in HV.
1H-NMR (400 MHz, DMSO-d 6): δ = 8.86 (d, 1H), 8.14 (s, 1H), 7.99 (d, 1H), 7.88 (d, 2H), 7.80 (d, 1H), 7.71-7.77 (m, 1H), 7.59-7.70 (m, 3H), 6.25 (d, 1H), 1.18 (s, 9H)。
Embodiment 11A
{ (E)-[3-(trifluoromethyl) phenyl] methene base } carboxylamine tertiary butyl ester
Figure 121528DEST_PATH_IMAGE033
Salt of wormwood heated drying in HV of consumption 10.88 g (78.73 mmol) is cooled to RT in argon gas, then with the THF of 127 ml and with the sulfonyl compound blending of the embodiment 10A of 5.45 g (13.12 mmol).Mixture stirs 16 hours in argon gas under refluxing.Mixture is cooled to room temperature, then filters via Celite (Celite).The latter uses THF rinsing.Then whole filtrate remove volatile constituent on rotatory evaporator in HV, obtains the title compound of 3.63 g (theoretical value 100%).
MS [DCI]: m/z = 274 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 8.95 (s, 1H), 8.26 (s, 1H), 8.23 (d, 1H), 8.01 (d, 1H), 7.80 (t, 1H), 1.52 (s, 9H)。
Embodiment 12A
2-nitro-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 765569DEST_PATH_IMAGE034
The compound of the embodiment 11A of 3.6 g (13.17 mmol) is incorporated in the Nitromethane 99Min. of 26 ml, then with the DIPEA blending of 0.69 ml (3.95 mmol).Mixture at room temperature stirs 2 hours.Reaction mixture dilutes by ethyl acetate, then in succession uses 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and then by saturated sodium-chloride water solution washed twice separately, dry on sodium sulfate, then concentrated on rotatory evaporator.Under refluxing, by residue, (approximately 5 g) are dissolved in the Virahol of 15 ml.After cooling, the product of precipitation is separated by filtering, and uses a small amount of washed with isopropyl alcohol, then blots.After further dry in HV, obtain title compound: 2.26 g (theoretical value 51%).
LC/MS [method 3]: R t=1.33 min; ES -: m/z=333 (M-H) -
1H-NMR (400 MHz, DMSO-d 6): δ = 7.88 (d, 1H), 7.78 (s, 1H), 7.70 (t, 2H), 7.59-7.65 (m, 1H), 5.31-5.44 (m, 1H), 4.97 (dd, 1H), 4.72-4.82 (m, 1H), 1.36 (s, 9H)。
Embodiment 13A
2-nitro-1-[3-(trifluoromethyl) phenyl] ethylamine hydrochloride
Figure 308545DEST_PATH_IMAGE035
The mixture of the embodiment 12A of 340 mg (1.02 mmol) at room temperature with 6.8 ml by hydrogenchloride two the 4N solution blending forming in alkane, then stirs 1 hour.Reaction mixture is under reduced pressure concentrated and dry in HV.This obtains the title compound of 274 mg (theoretical value 99%).
LC/MS [method 4]: R t=0.54 min; M/z=235 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 8.98 (br.s, 3H), 8.05 (s, 1H), 7.92 (d, 1H), 7.83 (d, 1H), 7.72 (t, 1H), 5.17-5.36 (m, 3H)。
Embodiment 14A
{ (phenyl sulfonyl) [2-(trifluoromethyl) phenyl] methyl } carboxylamine tertiary butyl ester
Figure 458084DEST_PATH_IMAGE036
According to the mode identical with embodiment 10A, obtain title compound (4.09 g, theoretical value 34%) from 2-(trifluoromethyl) phenyl aldehyde of 5.00 g (28.7 mmol).
1H-NMR (400 MHz, DMSO-d 6): δ = 8.88 (d, 1H), 8.20 (d, 1H), 7.79-7.88 (m, 5H), 7.68 (q, 3H), 6.32 (d, 1H), 1.19 (s, 9H)。
Embodiment 15A
{ (E)-[2-(trifluoromethyl) phenyl] methene base } carboxylamine tertiary butyl ester
Figure 965420DEST_PATH_IMAGE037
According to the mode identical with embodiment 11A, obtain title compound from the compound of the embodiment 14A of 4.09 g (9.85 mmol): 2.61 g (theoretical value 97%).
MS [DCI]: m/z = 274 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 9.02 (br.s, 1H), 8.25 (br.s, 1H), 7.90-7.97 (m, 1H), 7.85 (dd, 2H), 1.52 (s, 9H)。
Embodiment 16A
2-nitro-1-[2-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 882560DEST_PATH_IMAGE038
According to the mode identical with embodiment 12A, obtain title compound from the compound of the embodiment 15A of 1.50 g (5.49 mmol): 1.54 g (theoretical value 84%).
LC/MS [method 5]: R t=1.13 min; ES -: m/z=333 (M-H) -
1H-NMR (400 MHz, DMSO-d 6): δ = 8.04 (d, 1H), 7.80 (d, 1H), 7.70-7.77 (m, 2H), 7.55 (t, 1H), 5.72 (t, 1H), 4.77 (dd, 1H), 4.62-4.71 (m, 1H), 1.33 (s, 9H)。
Embodiment 17A
2-nitro-1-[2-(trifluoromethyl) phenyl] ethylamine hydrochloride
Figure 724614DEST_PATH_IMAGE039
According to the mode identical with embodiment 13A, from the compound of the embodiment 16A of 770 mg (2.30 mmol), obtain title compound: 656 mg (quantitatively, light contamination).
LC/MS [method 2]: R t=0.99 min; M/z=235 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 9.22 (br.s, 3H), 8.11 (d, 1H), 7.83-7.91 (m, 2H), 7.70 (t, 1H), 5.32-5.41 (m, 1H), 5.14-5.21 (m, 2H)。
Embodiment 18A
[(2,3-dichlorophenyl) (phenyl sulfonyl) methyl] carboxylamine tertiary butyl ester
Figure 119824DEST_PATH_IMAGE040
According to the mode identical with embodiment 10A, obtain title compound from the 2,3 dichloro benzaldehyde of 5.00 g (28.6 mmol): 2.22 g (theoretical value 19%)
1H-NMR (400 MHz, DMSO-d 6): δ = 8.93 (d, 1H), 7.96 (d, 1H), 7.84 (d, 2H), 7.76 (d, 2H), 7.63-7.71 (m, 2H), 7.51 (t, 1H), 6.60 (d, 1H), 1.21 (s, 9H)。
Embodiment 19A
[(E)-(2,3-dichlorophenyl) methene base] carboxylamine tertiary butyl ester
Figure 747245DEST_PATH_IMAGE041
According to the mode identical with embodiment 11A, obtain title compound from the compound of the embodiment 18A of 2.22 g (5.33 mmol): 1.38 g (theoretical value 94%).
MS [DCI]: m/z = 274 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 9.11 (s, 1H), 8.01 (d, 1H), 7.92 (d, 1H), 7.52 (t, 1H), 1.52 (s, 9H)。
Embodiment 20A
2-nitro-1-[2-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 569708DEST_PATH_IMAGE042
According to the mode identical with embodiment 12A, obtain title compound from the compound of the embodiment 19A of 1.38g (5.03 mmol): 865 mg (theoretical value 51%).
LC/MS [method 5]: R t=1.17 min; M/z=333 (M-H) -
1H-NMR (400 MHz, DMSO-d 6): δ = 8.07 (d, 1H), 7.64 (d, 1H), 7.50 (d, 1H), 7.44 (t, 1H), 5.74 (t, 1H), 4.87 (d, 1H), 4.62 (t, 1H), 1.34 (s, 9H)。
Embodiment 21A
1-(2,3-dichlorophenyl)-2-nitro ethylamine hydrochloride
Figure 836741DEST_PATH_IMAGE043
According to the mode identical with embodiment 13A, from the compound of the embodiment 20A of 430 mg (1.28 mmol), obtain title compound: 363 mg (quantitatively, 90% purity).
LC/MS [method 6]: R t=0.54/0.61 min; M/z=234 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 9.03 (br.s, 3H), 7.81 (d, 1H), 7.78 (dd, 1H), 7.54 (t, 1H), 5.45 (dd, 1H), 5.22-5.28 (m, 2H)。
Embodiment 22A
2-amino-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 97958DEST_PATH_IMAGE044
The compound of the embodiment 12A of 248 mg (1.04 mmol) is joined in methyl alcohol, then with palladium (10%, on the gac) blending of 20 mg.Under barometric point and at room temperature hydrogenation carry out a night.Reaction mixture is filtered, and filtrate is under reduced pressure concentrated.This obtains the title compound of 300 mg (theoretical value 88%).
LC/MS [method 5]: R t=0.74 min; M/z=305 (M+H) +
1h-NMR (400 MHz, DMSO-d 6) (main rotational isomer): δ=7.51-7.72 (m, 4H), 7.44 (d, 1H), 4.50 (d, 1H), 2.63-2.77 (m, 2H), 1.63 (br. s, 2H), 1.36 (s, 9H).
Embodiment 23A
2-(formamido-)-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 766837DEST_PATH_IMAGE045
The compound of the embodiment 22A of 75 mg (0.25 mmol) is joined in the THF of 1.5 ml, then at 0 DEG C, be divided into the formic acid 4-nitrophenyl ester blending of several small portions and 43.25 mg (0.26 mmol).Mixture stirs 2 hours at 0 DEG C, then at room temperature stirs a night.On rotatory evaporator, except desolventizing, residue is in harmonious proportion in DMSO, is purified by preparation property HPLC (method 10).This obtains the title compound of 66 mg (theoretical value 81%).
LC/MS [method 2]: R t=2.01 min; M/z=333 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 8.08 (br.s, 1H), 7.97 (s, 1H), 7.51-7.66 (m, 5H), 4.71 (d, 1H), 3.40 (dt, 1H), 3.22-3.29 (m, 1H), 1.36 (s, 9H)。
Embodiment 24A
N-{2-amino-2-[3-(trifluoromethyl) phenyl] ethyl } carboxamide hydrochloride
The compound of the embodiment 23A of 66 mg (0.2 mmol) is incorporated in the methylene dichloride of 1.5 ml, then at room temperature with 1.56 ml by hydrogenchloride two
Figure 327579DEST_PATH_IMAGE002
the 4N solution blending forming in alkane.Reaction mixture at room temperature stirs 1 hour.Reaction mixture removes volatile constituent on rotatory evaporator, then dry in HV.This obtains the title compound of 50 mg (theoretical value 94%).
LC/MS [method 2]: R t=0.90 min; M/z=233 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 8.56 (br.s, 3H), 8.19 (br.s, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.76-7.81 (m, 2H), 7.70 (d, 1H), 4.51 (t, 1H), 3.50-3.71 (m, 2H)。
Embodiment 25A
2-(kharophen)-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 64591DEST_PATH_IMAGE047
By the N of the compound of the embodiment 22A of 75 mg (0.25 mmol) and 60 μ L (0.35 mmol), N-diisopropylethylamine joins in the methylene dichloride of 2.5 ml together, then at room temperature with the Acetyl Chloride 98Min. blending of 21 μ L (0.30 mmol).Mixture at room temperature stirs 1 hour.Reaction mixture dilutes by ethyl acetate, then in succession uses 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and then by saturated sodium-chloride water solution washed twice separately, dry on sodium sulfate, then on rotatory evaporator except desolventizing.The further dry title compound that obtains 88 mg (theoretical value 100%) in HV.
LC/MS [method 4]: R t=0.98 min; M/z=347 (M+H) +.
Embodiment 26A
N-{2-amino-2-[3-(trifluoromethyl) phenyl] ethyl } acetamide hydrochloride
According to the mode identical with embodiment 13A, obtain the title compound of 70 mg (theoretical value 72%) from embodiment 25A.
LC/MS [method 5]: R t=0.46 min; M/z=247 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 8.59 (br.s, 3H), 8.11 (t, 1H), 7.90 (s, 1H), 7.75-7.80 (m, 2H), 7.70 (d, 1H), 4.48 (d, 1H), 3.54-3.63 (m, 1H), 3.43-3.51 (m, 1H), 1.78 (s, 3H)。
Embodiment 27A
2-[(ethylsulfonyl) and amino]-1-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (racemoid)
Figure 80138DEST_PATH_IMAGE049
The solution of the compound (100 mg, 0.33 mmol) of embodiment 22A in 2 ml pyridines at room temperature with ethyl sulfonyl chloride (0.66 mmol) blending of 62 μ L, gained mixture stirs 1 hour.Then add the ethyl sulfonyl chloride of other 16 μ L (0.17 mmol).Mixture stirs 1 hour again, with ethyl acetate dilution, then by succession shaking separately and extract for twice with 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution.Dried over sodium sulfate and concentrated on rotatory evaporator for organic phase, residue is dry in HV.This obtains the title compound of 114 mg (theoretical value 88%).
LC/MS [method 3]: R t=1.24 min; M/z=297 (M+H-BOC) +
1H-NMR (400 MHz, DMSO-d 6): δ = 7.69 (br.s, 1H), 7.55-7.66 (m, 3H), 7.49 (br.d, 1H), 7.16 (br. t, 1H), 4.67-4.75 (m, 1H), 3.12-3.38 (m, 2H), 2.81-2.99 (m, 2H), 1.38 (s, 9H), 1.10 (t, 3H)。
By the chromatography (method 15a) going up mutually in chirality, title compound can be split as its two kinds of enantiomers-referring to embodiment 28A and 29A.
Embodiment 28A
2-[(ethylsulfonyl) and amino]-1-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (enantiomer I)
Figure 131883DEST_PATH_IMAGE049
The enantiomer of the first wash-out being obtained from the chromatographic separation Separation of Enantiomers of embodiment 27A by method 15a.
Chiral analysis HPLC [method 16]: R t=1.35 min.
Embodiment 29A
2-[(ethylsulfonyl) and amino]-1-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (enantiomer II)
Figure 407006DEST_PATH_IMAGE049
The enantiomer of the last wash-out being obtained from the chromatographic separation Separation of Enantiomers of embodiment 27A by method 15a.
Chiral analysis HPLC [method 16]: R t=4.02 min.
Embodiment 30A
2-[(methyl sulphonyl) and amino]-1-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (racemoid)
The solution of the compound of embodiment 22A (100 mg, 0.33 mmol) in the pyridine of 2 ml at room temperature with the methylsulfonyl chloride blending of 66 μ L (0.66 mmol), then stir 1 hour.Mixture dilutes by ethyl acetate, then in succession uses 1M hydrochloric acid, and the each self-oscillation of saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution extracts for twice.Dried over sodium sulfate and concentrated on rotatory evaporator for organic phase, residue is dry in HV.This obtains the title compound of 121 mg (theoretical value 96%).
LC/MS [method 5]: R t=1.04 min; ESI pos.:m/z=297 (M+H-BOC) +, ESI neg.:m/z=381 (M-H) -,
1H-NMR (400 MHz, DMSO-d 6): δ = 7.68 (br.s, 1H), 7.55-7.66 (m, 3H), 7.50 (br.d, 1H), 7.15 (br. t, 1H), 4.67-4.75 (m, 1H), 3.13-3.27 (m, 2H), 2.80 (s, 3H), 1.36 (s, 9H)。
Title compound can be split as that its two kinds of enantiomers-this realizes by the chromatography (method 15a) going up mutually in chirality referring to embodiment 31A and 32A-.
Embodiment 31A
2-[(methyl sulphonyl) and amino]-1-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (enantiomer I)
The enantiomer of the first wash-out being obtained from the chromatographic separation Separation of Enantiomers of embodiment 30A by method 15a.
Chiral analysis HPLC [method 16]: R t=1.74 min.
Embodiment 32A
2-[(methyl sulphonyl) and amino]-1-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (enantiomer II)
Figure 989931DEST_PATH_IMAGE050
The last wash-out enantiomer being obtained from the chromatographic separation Separation of Enantiomers of embodiment 30A by method 15a.
Chiral analysis HPLC [method 16]: R t=3.47 min.
Embodiment 33A
2-amino-1-[2-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 68746DEST_PATH_IMAGE051
At continuous flow hydrogenation apparatus (H-Cube, from Thales Nano, Budapest obtains, HC-2-SS type) in, the solution that the compound of the embodiment 16A of 770 mg (2.30 mmol) forms in the methyl alcohol of 135 ml carries out hydrogenation (condition: Raney nickel box, the flow rate of 1 ml/min, 45 DEG C, hydrogen normal pressure).Gained solution is concentrated on rotatory evaporator, and residue is dry tout court in HV.This obtains the title compound of 669 mg (theoretical value 95%).
LC/MS [method 2]: R t=1.39 min; M/z=305 (M+H) +
1h-NMR (400 MHz, DMSO-d 6) (main rotational isomer): δ=7.57-7.68 (m, 3H), 7.51 (br.d, 1H), 7.43 (t, 1H), 4.77 (br.s, 1H), 2.66 (dd, 1H), 2.58 (m, 1H), 1.51 (br. s, 2H), 1.35 (s, 9H).
Embodiment 34A
2-[(ethylsulfonyl) and amino]-1-[2-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (racemoid)
The solution of the compound (100 mg, 0.33 mmol) of embodiment 33A in 2 ml pyridines at room temperature with ethyl sulfonyl chloride (0.66 mmol) blending of 62 μ L, gained mixture stirs 1 hour.Then add the ethyl sulfonyl chloride of other 16 μ L (0.66 mmol).Mixture stirs 1 hour again, with ethyl acetate dilution, then by succession shaking separately and extract for twice with 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution.Dried over sodium sulfate and concentrated on rotatory evaporator for organic phase, residue is dry in HV.This obtains the title compound of 113 mg (theoretical value 87%).
LC/MS [method 3]: R t=1.24 min; M/z=297 (M+H-BOC) +
1H-NMR (400 MHz, DMSO-d 6): δ =7.75 (d, 1H), 7.65-7.71 (m, 2H), 7.44-7.50 (m, 2H), 7.31 (br. t, 1H), 4.95-5.05 (m, 1H), 3.03-3.18 (m, 2H), 2.84-3.03 (m, 2H), 1.35 (s, 9H), 1.12 (t, 3H)。
Title compound can be split as its two kinds of enantiomers-referring to embodiment 35A and 36A-by the chromatography (method 15a) going up mutually in chirality.
Embodiment 35A
2-[(ethylsulfonyl) and amino]-1-[2-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (enantiomer I)
Figure 400687DEST_PATH_IMAGE053
The first wash-out enantiomer being obtained from the chromatographic separation Separation of Enantiomers of embodiment 34A by method 15a.
Chiral analysis HPLC [method 16]: R t=1.65 min.
Embodiment 36A
2-[(ethylsulfonyl) and amino]-1-[2-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (enantiomer II)
Figure 351326DEST_PATH_IMAGE053
The last wash-out enantiomer being obtained from the chromatographic separation Separation of Enantiomers of embodiment 34A by method 15a.
Chiral analysis HPLC [method 16]: R t=2.86 min.
Embodiment 37A
2-[(methyl sulphonyl) and amino]-1-[2-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (racemoid)
Figure 46880DEST_PATH_IMAGE054
According to the preparation method identical with embodiment 30A, obtain the title compound of 119 mg (theoretical value 95%) from the compound (100 mg, 0.33 mmol) of embodiment 33A.
LC/MS [method 5]: R t=1.01 min; ESI pos:m/z=283 (M+H-BOC) +, ESI neg:m/z=381 (M-H) -
1H-NMR (400 MHz, DMSO-d 6): δ = 7.73 (d., 1H), 7.65-7.73 (m, 2H), 7.44-7.53 (m, 2H), 7.27 (br. t, 1H), 4.98-5.08 (m, 1H), 3.04-3.18 (m, 2H), 2.84 (s, 3H), 1.35 (s, 9H)。
Title compound can be split as its two kinds of enantiomers-referring to embodiment 38A and 39A-by the chromatography (method 15a) going up mutually in chirality.
Embodiment 38A
2-[(methyl sulphonyl) and amino]-1-[2-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (enantiomer I)
Figure 399364DEST_PATH_IMAGE054
The first wash-out enantiomer being obtained from the chromatographic separation Separation of Enantiomers of embodiment 37A by method 15a.
Chiral analysis HPLC [method 16]: R t=2.04 min.
Embodiment 39A
2-[(methyl sulphonyl) and amino]-1-[2-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (enantiomer II)
Figure 341912DEST_PATH_IMAGE054
The last wash-out enantiomer being obtained from the chromatographic separation Separation of Enantiomers of embodiment 37A by method 15a.
Chiral analysis HPLC [method 16]: R t=7.41 min.
Embodiment 40A
[2-amino-1-(2,3-dichlorophenyl) ethyl] carboxylamine tertiary butyl ester
Figure 842164DEST_PATH_IMAGE055
At continuous flow hydrogenation apparatus (H-Cube, from Thales Nano, Budapest obtains, HC-2-SS type) in, the solution that the compound of the embodiment 20A of 440 mg (1.31mmol) forms in the methyl alcohol of 100 ml carries out hydrogenation (condition: Raney nickel box, the flow rate of 1 ml/min, 40 DEG C, hydrogen normal pressure).Gained solution is concentrated on rotatory evaporator, and residue is dry tout court in HV.This obtains the title compound of 370 mg (theoretical value 91%).
LC/MS [method 5]: R t=0.76 min; M/z=305 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 7.55 (br.d, 1H) 7.51 (dd, 1H), 7.31-7.39 (m, 2H), 4.81-4.89 (m, 1H), 2.72 (dd, 1H), 2.59 (d, 1H), 1.66 (br. s, 2H), 1.36 (s, 9H)。
Embodiment 41A
1-(2,3-dichlorophenyl)-2-[(ethylsulfonyl) and amino] ethyl } carboxylamine tertiary butyl ester (racemoid)
Figure 262781DEST_PATH_IMAGE056
By using the method identical with embodiment 27A, from the title compound of compound (0.33 mmol) acquisition 101 mg of the embodiment 40A of 100 mg (theoretical value 78%).
LC/MS [method 3]: R t=1.21 min; ESI pos:m/z=297 (M+H-BOC) +; ESI neg:m/z=395 (M-H) -
1H-NMR (400 MHz, DMSO-d 6): δ = 7.56 (dd, 1H), 7.52 (br.d, 1H), 7.46 (dd, 1H), 7.39 (t, 1H), 7.29 (br. t, 1H),. 5.02-5.11 (m, 1H), 3.04-3.22 (m, 2H), 2.86-3.02 (m, 2H), 1.36 (s, 9H), 1.14 (t, 3H)。
Title compound can be split as its two kinds of enantiomers-referring to embodiment 42A and 43A-by the chromatography (method 15a) going up mutually in chirality.
Embodiment 42A
1-(2,3-dichlorophenyl)-2-[(ethylsulfonyl) and amino] ethyl } carboxylamine tertiary butyl ester (enantiomer I)
Figure 548400DEST_PATH_IMAGE057
The first wash-out enantiomer being obtained from the chromatographic separation Separation of Enantiomers of embodiment 41A by method 15a.
Chiral analysis HPLC [method 16]: R t=1.94 min.
Embodiment 43A
1-(2,3-dichlorophenyl)-2-[(ethylsulfonyl) and amino] ethyl } carboxylamine tertiary butyl ester (enantiomer II)
Figure 661849DEST_PATH_IMAGE057
The last wash-out enantiomer being obtained from the chromatographic separation Separation of Enantiomers of embodiment 41A by method 15a.
Chiral analysis HPLC [method 16]: R t=3.67 min.
Embodiment 44A
1-(2,3-dichlorophenyl)-2-[(methyl sulphonyl) and amino] ethyl } carboxylamine tertiary butyl ester (racemoid)
According to the preparation method identical with embodiment 30A, obtain the title compound of 113 mg (theoretical value 90%) from the compound (100 mg, 0.33 mmol) of embodiment 40A.
LC/MS [method 5]: R t=1.05 min; ESI pos:m/z=283 (M+H-BOC) +, ESI neg:m/z=381 (M-H) -
1H-NMR (400 MHz, DMSO-d 6): δ = 7.56 (dd, 1H), 7.53 (br.d, 1H), 7.47 (dd, 1H), 7.39 (t, 1H), 7.24 (t, 1H), 5.05-5.15 (m, 1H), 3.05-3.23 (m, 2H), 2.85 (s, 3H), 1.38 (s, 9H)。
Title compound can be split as that its two kinds of enantiomers-this realizes by the chromatography (method 15a) going up mutually in chirality referring to embodiment 45A and 46A-.
Embodiment 45A
1-(2,3-dichlorophenyl)-2-[(methyl sulphonyl) and amino] ethyl } carboxylamine tertiary butyl ester (enantiomer I)
Figure 873705DEST_PATH_IMAGE058
The first wash-out enantiomer being obtained from the chromatographic separation Separation of Enantiomers of embodiment 44A by method 15a.
Chiral analysis HPLC [method 16]: R t=1.88 min.
Embodiment 46A
1-(2,3-dichlorophenyl)-2-[(methyl sulphonyl) and amino] ethyl } carboxylamine tertiary butyl ester (enantiomer II)
Figure 751181DEST_PATH_IMAGE058
The last wash-out enantiomer being obtained from the chromatographic separation Separation of Enantiomers of embodiment 44A by method 15a.
Chiral analysis HPLC [method 16]: R t=10.30 min.
Embodiment 47A
N-{2-amino-2-[3-(trifluoromethyl) phenyl] ethyl } Toluidrin hydrochloride (enantiomer II)
The solution being formed in the methylene dichloride of 2 ml by the compound of the embodiment 32A of 57 mg (0.15 mmol) and 2 ml by hydrogenchloride two
Figure 510375DEST_PATH_IMAGE002
the 4N solution blending forming in alkane, then at room temperature stirs 2 hours.On rotatory evaporator, remove volatile constituent.The methylene dichloride blending of residue and 5 ml, these components are stirred in together, and then mixture is again concentrated on rotatory evaporator, then dry in HV.This obtains the title compound of 52 mg (quantitatively), 85% purity.
LC/MS [method 3]: R t=0.55 min; ESI pos.:m/z=283 (M+H) +
Same method is for the preparation of embodiment 48A-58A:
Figure 538374DEST_PATH_IMAGE060
Figure 533006DEST_PATH_IMAGE061
Embodiment 59A
2-hydroxyl-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 784996DEST_PATH_IMAGE062
N-tert-butoxycarbonyl-2-(3-trifluoromethyl)-DL-glycine of 4.00 g (12.5 mmol) and the solution of the triethylamine of 2.1 ml (15 mmol) in the THF of 50 ml are cooled to 0 DEG C, and the chloroformic acid isobutyl that then drips 1.79 ml (13.8 mmol) is carried out blending.The stiff suspension obtaining stirs 1 hour at 0 DEG C again, is then filled in cold flask.Solids washs with a small amount of TH, and whole filtrate is slowly added drop-wise to (venting strongly) in the ice-cooled suspension of sodium borohydride (1.42 g, 37.6 mmol) in the water of 6 ml.Mixture acutely stirs 1 hour at 0 DEG C again, then, with the 1N hydrochloric acid blending of 5 ml, is then extracted with ethyl acetate three times.Organic phase is washed by 1N aqueous sodium hydroxide washes, then uses saturated sodium bicarbonate aqueous solution washed twice, by dried over sodium sulfate, and concentrated on rotatory evaporator.Preparation property HPLC purification (method 10) for residue.This obtains the title compound (theoretical value 52%) of 2.00 g.
LC/MS [method 5]: R t=1.02 min; M/z=328 (M+Na) +, 206 (M+H-BOC) +.
1H NMR (DMSO-d 6, 00 MHz): δ = 7.65 (s, 1H), 7.51-7.62 (m, 3H), 7.37 (br. d, 1H), 4.86 (t, 1H), 4.57-4.66 (m, 1H), 3.46-3.58 (m, 2H), 1.37 (s, 9H)。
Embodiment 60A
Carboxylamine 2-amino-2-[3-(trifluoromethyl) phenyl] ethyl ester hydrochloride
The solution of the compound of the embodiment 59A of 1.00 g (3.28 mmol) in the acetonitrile of 20 ml is cooled to-15 DEG C, then with the chloro sulfonyl isocyanate blending of 399 μ L (4.59 mmol).After 10 minutes, add the water of 18 ml, mixture heats 2 hours at 60 DEG C.After being cooled to room temperature, solution becomes alkalescence (pH 9-10) by adding saturated sodium bicarbonate aqueous solution, is then extracted with ethyl acetate three times.The organic phase dried over sodium sulfate merging is then removed desolventizing on rotatory evaporator.In order to realize the amino protection of going completely, residue and 15 ml by hydrogenchloride two
Figure 126296DEST_PATH_IMAGE064
the 4M solution blending forming in alkane, this mixture at room temperature stirs 5 minutes, then concentrated on rotatory evaporator.Dry in HV of residue obtains the title compound of 785 mg (theoretical value 84%).
LC/MS [method 4]: R t=0.44 min; M/z=249 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 8.80 (br.s, 3H), 7.97 (s, 1H), 7.88 (d, 1H), 7.80 (d, 1H), 7.70 (t, 1H), 6.61 (br. s, 2H), 4.63-4.73 (m, 1H), 4.26-4.38 (m, 2H)。
Embodiment 61A
2-amino-2-[2-(trifluoromethyl) phenyl] ethylate hydrochlorate
(2-trifluoromethyl)-DL-glycine of consumption 500 mg (2.28 mmol) is divided into several parts and in argon atmosphere, adds the use ice water-cooled 1M borine-THF complex solution (9.13 ml, 9.13 mmol) forming in THF.After 10 minutes, remove cooling bath, mixture at room temperature stirs 4 hours.For aftertreatment, by the interpolation of 1N hydrochloric acid, pH regulator is extremely acid, on rotatory evaporator, remove THF, 1N aqueous sodium hydroxide solution neutralization for the remaining aqueous solution, is then adjusted to alkalescence with saturated sodium bicarbonate aqueous solution.It is extracted with ethyl acetate three times.The organic phase dried over sodium sulfate merging is then removed desolventizing on rotatory evaporator.The thick amino alcohol obtaining and 15 ml by hydrogenchloride two
Figure 601587DEST_PATH_IMAGE064
the 4M solution blending forming in alkane, then stirs 5 minutes.Solution is then concentrated on rotatory evaporator.Dry the obtain title compound (550 mgs, quantitative) of residue in HV, it just can further participate in reaction without purifying.
LC/MS [method 2]: R t=0.78 min; M/z=206 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.71 (br.s, 3H), 7.92 (d, 1H), 7.78-7.86 (m, 2H), 7.64 (t, 1H), 5.75 (t, 1H), 4.42 (dd, 1H), 3.64-3.77 (m, 2H)。
Embodiment 62A
2-hydroxyl-1-[2-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 988706DEST_PATH_IMAGE066
The compound of the embodiment 61A of 367 mg (1.52 mmol) is dissolved in to two of 20 ml in the 5% concentration sodium bicarbonate aqueous solution of alkane and 20 ml, heavy carbonic di-t-butyl ester (Di-tert.-butyldicarbonat) blending of this solution and 356 μ L (1.55 mmol), then mixture at room temperature stirs a night.It is extracted with ethyl acetate five times.The organic phase dried over sodium sulfate merging, then concentrated on rotatory evaporator.This residue is corresponding to title compound (338 mg, theoretical value 73%).
LC/MS [method 2]: R t=2.01 min; M/z=306 (M+H) +
1h NMR (DMSO-d 6400 MHz) (rotational isomer): δ=7.61-7.71 (m, 3H), 7.37-7.48 (m, 2H), 4.90-5.01 (m, 2H), 3.35-3.50 (m, 2H), 1.35 (br.s approximately 7.5 H)+1.10 (br.s, 1.5 H).
Embodiment 63A
Carboxylamine 2-amino-2-[2-(trifluoromethyl) phenyl] ethyl ester hydrochloride
The solution that the compound of the embodiment 62A of 570 mg (1.87 mmol) forms in the acetonitrile of 100 ml is cooled to-15 DEG C, then with the chloro sulfonyl isocyanate blending of 325 μ L (3.73 mmol).After 10 minutes, add the water of 50 ml, mixture heats 4 hours at 60 DEG C.After being cooled to room temperature, solution becomes alkalescence (pH 9-10) by adding saturated sodium bicarbonate aqueous solution, is then extracted with ethyl acetate three times.The organic phase dried over sodium sulfate merging is then removed desolventizing on rotatory evaporator.In order to realize the amino protection of going completely, residue and 15 ml by hydrogenchloride two
Figure 918595DEST_PATH_IMAGE064
the 4M solution blending forming in alkane, this mixture at room temperature stirs 5 minutes, then on rotatory evaporator, removes volatile constituent.This residue is corresponding to title compound (630 mg, quantitative).
LC/MS [method 4]: R t=0.34 min; M/z=249 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ =8.97 (br.s, 3H), 8.06 (d, 1H), 7.80-7.87 (m, 2H), 7.66 (t, 1H), 6.64 (br.s, 2H), 4.64 (br.s, 1H), 4.37 (dd, 1H), 4.27 (dd, 1H)。
Embodiment 64A
[(1R)-1-(3-chloro-phenyl-)-2-hydroxyethyl] carboxylamine tertiary butyl ester
According to the mode identical with embodiment 62A, obtain the title compound of 166 mg (theoretical value 95%) from (2R)-2-amino-2-(3-chloro-phenyl-) ethane-1-alcohol of 134 mg (0.644 mmol).
LC/MS [method 1]: R t=1.10 min; M/z=272 (M+H-BOC) +.
Embodiment 65A
Carboxylamine 2-amino-2-(3-chloro-phenyl-) ethyl ester hydrochloride
Figure 763240DEST_PATH_IMAGE069
According to the mode identical with embodiment 60A, obtain the title compound of 200 mg from the compound of the embodiment 64A of 166 mg (0.61 mmol), be then further used as crude product and use.
LC/MS [method 4]: R t=0.30 min; M/z=215 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 8.71 (br.s, 3H), 7.66 (s, 1H), 7.46-7.54 (m, 3H), 6.62 (br. s, 2H), 4.52-4.62 (m, 1H), 4.22-4.32 (m, 2H)。
Embodiment 66A
2-amino-2-(2-chloro-phenyl-) ethanol
Figure 586971DEST_PATH_IMAGE070
(2-chloro-phenyl-)-DL-glycine of consumption 4.00 g (21.6 mmol) is divided into several parts and in argon atmosphere, adds the use ice water-cooled 1M borine-THF complex solution (64.7ml, 64.7 mmol) forming in THF.After 10 minutes, remove cooling bath, mixture at room temperature stirs 4 hours.For aftertreatment, add at leisure several flake ices, until gas is emitted end.Mixture is adjusted to alkalescence by adding 1N aqueous sodium hydroxide solution, then with MTBE extraction three times.The organic phase dried over sodium sulfate merging, then concentrated on rotatory evaporator.The thick title compound that obtains (3.00 g, theoretical value 77%) further reacts in the situation that not purifying in addition.
LC/MS [method 4]: R t=0.22 min; M/z=172 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 7.64 (d, 1H), 7.37 (d, 1H), 7.32 (t, 1H), 7.24 (t, 1H), 4.87 (br.s, 1H), 4.26-4.32 (m, 1H), 3.53 (dd, 1H), 3.20 (dd, 1H), 2.08 (br. s, 2H)。
Embodiment 67A
[1-(2-chloro-phenyl-)-2-hydroxyethyl] carboxylamine tertiary butyl ester
Figure 554927DEST_PATH_IMAGE071
Together with the heavy carbonic di-t-butyl ester of the compound of the embodiment 66A of 2.3 g (13.4 mmol) and 3.69 ml (16 mmol), be stirred in the acetonitrile of 100 ml.Then add ethyl acetate and saturated sodium bicarbonate aqueous solution.Separate two-phase, water is extracted with ethyl acetate twice again.The organic phase merging is water (2 times) and saturated sodium-chloride water solution washing in succession, by dried over sodium sulfate and concentrated on rotatory evaporator.Residue is dry in HV.(4.2 g) react in the situation that not purifying in addition in embodiment 68A for the thick title compound that obtains.
LC/MS [method 6]: R t=2.02 min; M/z=272 (M+H) +
1H NMR (DMSO-d 6, 400 MHz) (rotamers): δ = 7.43 (dd, 1H), 7.39 (dd, 1H), 7.36 (br.d, 1H), 7.32 (td, 1H), 7.25 (td, 1H), 4.94-5.02 (m, 1H), 4.91 (t, 1H), 3.46-3.54 (m, 1H), 3.35-3.43 (m, 1H), 1.36 (br. s, 7.5 H) + 1.16 (br. s, 1.5 H)。
Embodiment 68A
Carboxylamine 2-amino-2-(2-chloro-phenyl-) ethyl ester hydrochloride
Figure 651058DEST_PATH_IMAGE072
According to the mode identical with embodiment 63A, obtain title compound (1.10 g, 69% of theoretical value, through 2 stages) from the compound of the embodiment 67A of 2.00 g (7.36 mmol).
LC/MS [method 4]: R t=0.28 min; M/z=215 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.76 (br.s, 3H), 7.75 (d, 1H), 7.57 (dd, 1H), 7.41-7.53 (m, 2H), 6.64 (br.s, 2H), 4.82-4.92 (m, 1H), 4.27 (qd [ABX], 2H)。
Embodiment 69A
(2R)-2-amino-2-[3-(trifluoromethyl) phenyl] propane-1-alcohol hydrochloride
Figure 424979DEST_PATH_IMAGE073
The 1M solution (37.1 ml, 37.1 mmol) of the borine-tetrahydrofuran (THF) title complex forming in THF is cooled to 0 DEG C in argon gas.Add therein (2R)-2-amino-2-[3-(trifluoromethyl) phenyl of 2.5 g (9.27 mmol)] propionic acid, and after removing cooling bath, mixture at room temperature stirs 4 hours.For aftertreatment, it carries out acidifying with 1N hydrochloric acid carefully.On rotatory evaporator, remove THF.Water is adjusted to alkalescence with saturated sodium bicarbonate aqueous solution, is then extracted with ethyl acetate three times.The organic phase dried over sodium sulfate merging, then concentrated on rotatory evaporator.(2.4 g) the further reactions in the situation that not purifying of gained crude product.
LC/MS [method 2]: R t=0.93 min; M/z=218 (M+H) +.
Embodiment 70A
(2R)-1-hydroxyl-2-[3-(trifluoromethyl) phenyl] and propane-2-yl } carboxylamine tertiary butyl ester
The compound of the embodiment 69A of 2.032 g (9.27 mmol) is dissolved in to two of the methylene dichloride of 50 ml and 10 ml
Figure 242074DEST_PATH_IMAGE075
in alkane, the then heavy carbonic di-t-butyl ester blending of gained solution and 2.17 ml (9.45 mmol).Mixture at room temperature stirs a night, then on rotatory evaporator, removes volatile constituent.This residue is dry in HV, is then purified by preparation property HPLC (method 10).This obtains the title compound of 2.69 g (91%, by the theoretical value in 2 stages).
LC/MS [method 5]: R t=1.09 min; M/z=342 (M+Na) +.
1h NMR (DMSO-d 6, 400 MHz) and (rotational isomer): δ=7.50-7.64 (m, 5H), 6.92 (br. s, 1H), 4.97 (br. t, 1H), 3.43-3.54 (m [AB], 3H), 1.58 (s, 3H), 1.34+1.00 (2 br.s amount to 9H).
Embodiment 71A
Carboxylamine (2R)-2-amino-2-[3-(trifluoromethyl) phenyl] propyl diester hydrochloride
The solution that the compound of the embodiment 70A of 520 mg (1.63 mmol) forms in the acetonitrile of 10ml is cooled to-15 DEG C, then with the chloro sulfonyl isocyanate blending of 198 μ L (2.28 mmol).After 10 minutes, add the water of 18 ml, mixture heats a night at 60 DEG C.After being cooled to room temperature, solution is adjusted to alkalescence by adding saturated sodium bicarbonate aqueous solution, is then extracted with ethyl acetate three times.The organic phase dried over sodium sulfate merging is then removed desolventizing on rotatory evaporator.In order to realize the amino protection of going completely, residue and 5ml by hydrogenchloride two
Figure 137535DEST_PATH_IMAGE064
the 4M solution blending forming in alkane, this mixture at room temperature stirs 5 minutes, then concentrated on rotatory evaporator.Dry in HV of residue obtains title compound (440 mg, theoretical value 90%).
LC/MS [method 4]: R t=0.47 min; M/z=263 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 8.80 (br.s, 3H), 7.97 (s, 1H), 7.88 (d, 1H), 7.80 (d, 1H), 7.70 (t, 1H), 6.61 (br. s, 2H), 4.63-4.73 (m, 1H), 4.26-4.38 (m, 2H)。
Embodiment 72A
(2R)-2-[(tert-butoxycarbonyl) amino]-2-(2-chloro-phenyl-) propionic acid
Figure 935857DEST_PATH_IMAGE077
(2R)-2-amino-2-[2-(chloromethyl) phenyl of consumption 500 mg (2.11 mmol)] propionic acid is dissolved in the 5% concentration sodium hydrogen carbonate solution of 10 ml, then with two of 10 ml
Figure 245616DEST_PATH_IMAGE064
alkane blending, then with the heavy carbonic di-t-butyl ester blending of 511 μ L (2.22 mmol).Mixture stirs a night, is adjusted to carefully 2 pH value with 1N hydrochloric acid, is then extracted with ethyl acetate three times.The organic phase dried over sodium sulfate merging, then concentrated on rotatory evaporator.Residue (322 mg, theoretical value 51%) is corresponding to title compound, and former state own can further be reacted.
LC/MS [method 3]: R t=1.08 min; M/z=322 (M+Na) +.
Embodiment 73A
[(2R)-2-(2-chloro-phenyl-)-1-hydroxyl third-2-yl] carboxylamine tertiary butyl ester
Figure 378657DEST_PATH_IMAGE078
According to the mode identical with embodiment 59A, obtain the title compound (theoretical value 77%) of 110 mg from the compound of the embodiment 72A of 150 mg (0.5 mmol).
LC/MS [method 4]: R t=0.98 min; M/z=286 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 7.44 (d, 1H), 7.32 (d, 1H), 7.17-7.29 (m, 2H), 6.79 (br. s, 1H), 4.96 (br. t, 1H), 3.60-3.82 (m, 2H), 1.64 (s, 3H), 1.33 (s, 9H)。
Embodiment 74A
(2R)-2-amino-2-(2-chloro-phenyl-) propane-1-alcohol hydrochloride
According to the mode identical with embodiment 47A, by using hydrogenchloride two
Figure 271844DEST_PATH_IMAGE064
the 4N solution forming in alkane is processed, and obtains the title compound of 49 mg (about 85% purity) from the compound of the embodiment 73A of 55 mg (0.19 mmol).It just can participate in reaction without purifying.
LC/MS [method 5]: R t=0.28 min; M/z=186 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.63 (br.s, 3H), 7.52 (d, 1H), 7.34-7.49 (m, 3H), 5.69 (br.s, 1H), 4.11 (dd, 1H), 3.83 (dd, 1H), 1.70 (s, 3H)。
Embodiment 75A
Carboxylamine (2R)-2-amino-2-(2-chloro-phenyl-) propyl diester
Figure 580202DEST_PATH_IMAGE080
The solution that the compound of the embodiment 73A of 55 mg (0.19 mmol) forms in the acetonitrile of 2 ml is divided into 3 parts at room temperature through the time of 20 minutes and the chloro sulfonyl isocyanate blending of 39 μ L (0.42 mmol).After other 10 minutes, add the water of 2 ml, mixture heats 2 hours at 60 DEG C.After being cooled to room temperature, solution is adjusted to alkalescence by adding 2N sodium bicarbonate aqueous solution, is then extracted with ethyl acetate three times.The organic phase dried over sodium sulfate merging, then concentrated on rotatory evaporator.The dry title compound (34 mgs, 77%, 90% purity of theoretical value) that obtain slight pollution of residue in HV, itself former state just can further participate in reaction.
1H NMR (DMSO-d 6, 400 MHz): δ = 7.76 (dd, 1H), 7.38 (dd, 1H), 7.32 (td, 1H), 7.26 (td, 1H), 6.27-6.51 (br. s, 2H), 4.36 (d, 1H), 4.24 (d, 1H), 2.11-2.42 (br.s, 2H), 1.48 (s, 3H)。
Embodiment 76A
3-(4-chloro-phenyl-)-5-oxo-4-[(1E) and-3,3,3-trifluoropropyl-1-alkene-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetic acid methyl ester
Figure 872643DEST_PATH_IMAGE081
The compound of the embodiment 7A of 280 mg (0.74 mmol) is at room temperature added in the pyridine of 5.3 ml with together with the 4-dimethylaminopyridine of 108.1 mg (0.89 mmol), with the trifluoromethanesulfanhydride anhydride blending of 0.31 ml (1.84 mmol) of several parts, then stir 12 hours.On rotatory evaporator, remove pyridine, this residue is in harmonious proportion in acetonitrile and 1N hydrochloric acid.Preparation property HPLC purification (method 10) for product.This obtains the title compound of 230 mg (theoretical value 86%).
LC/MS [method 4]: R t=1.14 min; M/z=362 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 7.68 (s, 4H), 7.18 (d, 1H), 6.85 (dd, 1H), 4.78 (s, 2H), 3.72 (s, 3H)。
Embodiment 77A
3-(4-chloro-phenyl-)-5-oxo-4-[(1E) and-3,3,3-trifluoropropyl-1-alkene-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetic acid
Figure 792057DEST_PATH_IMAGE082
The compound of the embodiment 76A of 260 mg (0.72 mmol) is dissolved in the methyl alcohol of 5 ml, then with the 1M lithium hydroxide aqueous solution blending of 2.87 ml (2.87 mmol).Mixture at room temperature stirs 1 hour, then carries out acidifying with 1N hydrochloric acid, and dilutes with DMSO.Preparation property HPLC purification (method 10) for whole solution.This obtains the title compound of 215 mg (theoretical value 86%).
LC/MS [method 4]: R t=1.03 min; M/z=348 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 13.31 (br. s, 1H), 7.68 (s, 4H), 7.19 (dd, 1H), 6.79-6.92 (m, 1H), 4.64 (s, 2H)。
Embodiment 78A
3-amino-3-[3-(trifluoromethyl) phenyl] propane-1-alcohol hydrochloride
Figure 486344DEST_PATH_IMAGE083
With ice-cooled and in argon gas, introduce 1M borine-THF complex solution of 2.57 ml (2.57 mmol) 3-amino-3-[3-(trifluoromethyl) phenyl with 150 mg (0.64 mmol)] propionic acid blending.After 10 minutes, remove cooling bath, mixture at room temperature stirs 4 hours.Using ice-cooled in the situation that, dripping the 3N aqueous sodium hydroxide solution of 1 ml, then mixture stirs a night.Reaction soln carries out acidifying with 1N hydrochloric acid.On rotatory evaporator, remove THF, preparation property HPLC purification (method 10) for the aqueous solution obtaining.This obtains the title compound of 160 mg (theoretical value 97%).
LC/MS [method 1]: R t=1.08 min; M/z=220 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.19 (s, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.74 (d, 1H), 7.66 (t, 1H), 4.42 (dd, 1H), 3.40 (dt, 1H), 3.25 (ddd, 1H), 2.04-2.16 (m, 1H), 1.87-1.97 (m, 1H)。
Embodiment 79A
(1S)-3-hydroxyl-1-[2-(trifluoromethyl) phenyl] and propyl group } carboxylamine tertiary butyl ester
Figure 137905DEST_PATH_IMAGE084
With ice-cooled and in argon gas, introduce 1M borine-THF complex solution of 6 ml (6 mmol) and with (S)-Boc-2-(trifluoromethyl)-beta-phenyl L-Ala (500 mg, 1.50 mmol) blending.Mixture stirs 1 hour at 0 DEG C.In order to remove excessive borine, add the ice of several.After gas is emitted end, add saturated sodium bicarbonate aqueous solution, this mixture is extracted with ethyl acetate.1N HCl acidifying for water, is then extracted with ethyl acetate twice.1N salt acid elution for the organic phase of these merging, then with saturated sodium-chloride water solution washing, by dried over sodium sulfate, and concentrated on rotatory evaporator.This residue is dry and corresponding to title compound (340 mg, theoretical value 71%) in HV.
LC/MS [method 3]: R t=1.15 min; M/z=220 (M+H-BOC) +.
embodiment 80A
(3S)-3-amino-3-[2-(trifluoromethyl) phenyl] propane-1-alcohol hydrochloride
Figure 996270DEST_PATH_IMAGE085
The compound of the embodiment 79A of 150 mg (0.47 mmol) 3 ml by hydrogenchloride two
Figure 391480DEST_PATH_IMAGE064
in the 4N solution forming in alkane, stir 20 minutes.On rotatory evaporator, remove volatile constituent, then residue is dry in HV.This obtains the title compound of 140 mg (theoretical value 87%).
LC/MS [method 3]: R t=1.15 min; M/z=220 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.69 (br.s, 3H), 7.98 (d, 1H), 7.73-7.89 (m, 2H), 7.62 (t, 1H), 4.59 (br.s, 1H), 3.61-3.81 (m, 1H), 3.40-3.48 (m, 2H), 2.10-2.22 (m, 1H), 1.92-2.02 (m, 1H)。
embodiment 81A
Carboxylamine (3S)-3-amino-3-[2-(trifluoromethyl) phenyl] propyl diester hydrochloride
According to the mode identical with embodiment 63A, obtain the title compound of 190 mg (theoretical value 90%) from the compound of the embodiment 79A of 180 mg (0.70 mmol).
LC/MS [method 2]: R t=0.97 min; M/z=263 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.72 (br.s, 3H), 7.99 (d, 1H), 7.80-7.87 (m, 2H), 7.65 (t, 1H), 6.50 (br.s, 2H), 4.48-4.60 (m, 1H), 3.77-3.93 (m, 2H), 2.29-2.39 (m, 1H), 2.12-2.23 (m, 1H)。
embodiment 82A
3-[(tert-butoxycarbonyl) amino]-3-(2,3-dichlorophenyl) propionic acid
Figure 903681DEST_PATH_IMAGE087
3-amino-3-(2,3-dichlorophenyl) propionic acid of consumption 1.50 g (6.41 mmol) is suspended in two of 45 ml
Figure 233031DEST_PATH_IMAGE064
in the 5% concentration sodium bicarbonate aqueous solution of alkane and 45 ml, this suspension at room temperature with the heavy carbonic di-t-butyl ester blending of 1.40 g (6.41 mmol).Mixture at room temperature stirs 16 hours.For aftertreatment, the under agitation ethyl acetate blending of this suspension and approximately 50 ml.Throw out by suction filtration out.After being separated of mother liquor, water is adjusted to 1 pH value carefully with 1N hydrochloric acid, then extract once by the ethyl acetate of approximately 50 ml.The organic phase dried over sodium sulfate merging, filters and under reduced pressure concentrates.This obtains the target compound of 1.68 g (theoretical value 79%).
LC-MS [method 3] Rt=1.18 min; MS [ESIneg]: m/z=332 (M-H) -
Obtain similarly following compounds:
Figure 431931DEST_PATH_IMAGE088
Embodiment 85A
[1-(2,3-dichlorophenyl)-3-hydroxypropyl] carboxylamine tertiary butyl ester
The THF neutralization that the compound of the embodiment 82A of 430 mg (1.29 mmol) is suspended in to 5 ml is cooled to 0 DEG C, the triethylamine of this suspension and 179 μ L (1.29 mmol) and with the isobutyl chlorocarbonate blending of 184 μ L (1.42 mmol), then at 0 DEG C, stir 1 hour.Then suspension be filled in chilled flask via plug thatch (Seitz) sintered glass material, and remaining solid washs with a small amount of THF.With under ice-cooled, filtrate is added drop-wise in the solution that the sodium borohydride of 146 mg (3.86 mmol) forms in the water of 0.5 ml at leisure, then at 0 DEG C, stirs 1 hour.For aftertreatment, the saturated sodium bicarbonate aqueous solution blending of reaction mixture and approximately 10 ml, then extracts by the ethyl acetate of 50 ml.Organic phase with saturated sodium bicarbonate aqueous solution washing once and wash once with saturated sodium-chloride water solution.They,, by dried over sodium sulfate, filter and concentrate on rotatory evaporator.This obtains the target compound of 419 mg (theoretical value 95%).
LC-MS [method 3] Rt=1.20 min; MS [ESIpos]: m/z=342 (M+Na) +
Obtain similarly following compounds:
Figure 907223DEST_PATH_IMAGE090
embodiment 87A
[1-(2-fluorophenyl)-3-hydroxypropyl] carboxylamine tertiary butyl ester
Figure 661552DEST_PATH_IMAGE091
The compound of the embodiment 84A of 580 mg (1.95 mmol) is dissolved in to 1 of 5 ml, in 2-glycol dimethyl ether, gained solution at room temperature uses the sodium borohydride of 110.7 mg (2.93 mmol) and the lithium chloride of 16.5 mg (0.39 mmol) to mix in succession.Then mixture stirs 16 hours at 85 DEG C.For aftertreatment, the saturated soluble tartrate sodium water solution blending of it and 15 ml, then at every turn with the ethyl acetate extraction of 10 ml, totally three times.The organic phase dried over mgso merging, filters and concentrates on rotatory evaporator.Crude product is by silica gel chromatography purify (wash-out: cyclohexane/ethyl acetate 1:1).This obtains the target compound of 383 mg (theoretical value 73%).
LC-MS [method 4] R t=0.91 min; MS [ESIpos]: m/z=270 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 1.44 (s, 9H), 1.83-2.06 (m, 2H), 3.01 (br.s, 1H), 3.68 (br.s, 2H), 4.98-5.14 (m, 1H), 5.20-5.37 (m, 1H), 7.00-7.09 (m, 1H), 7.09-7.16 (m, 1H), 7.22-7.34 (m, 2H)。
Embodiment 88A
Carboxylamine 3-amino-3-(2,3-dichlorophenyl) propyl diester
Figure 460881DEST_PATH_IMAGE092
According to the mode identical with embodiment 63A, obtain the title compound of the crude product form of 572 mg (quantitatively) from the compound of the embodiment 85A of 612 mg.
1H NMR (DMSO-d 6, 400 MHz): δ = 8.58 (br.s, 3H), 7.72 (dd, 2H), 7.53 (t, 1H), 6.53 (br.s, 2H), 4.75-4.87 (m, 1H), 3.92 (dt, 1H), 3.73-3.80 (m, 1H), 2.22-2.32 (m, 1H), 2.07-2.19 (m, 1H)。
embodiment 89A
Carboxylamine 3-amino-3-(2-fluorophenyl) propyl diester hydrochloride
Figure 984266DEST_PATH_IMAGE093
Since the compound of the embodiment 87A of 380 mg, according to mode identical in embodiment 63A, obtain the target compound of 268 mg (theoretical value 76%).
1H-NMR (400 MHz, DMSO-d 6): δ = 2.05-2.21 (m, 1H), 2.25-2.40 (m, 1H), 3.62-3.75 (m, 1H), 3.81-3.93 (m, 1H), 4.50-4.66 (m, 1H), 6.53 (br.s, 2H), 7.23-7.37 (m, 2H), 7.41-7.52 (m, 1H), 7.62-7.75 (m, 1H), 8.64 (br.s, 3H)。
embodiment 90A
3-amino-3-(2,3-dichlorophenyl) propane-1-alcohol
Figure 224230DEST_PATH_IMAGE094
The compound of the embodiment 85A of 800 mg (2.50 mmol) is dissolved in the methylene dichloride of 20 ml, then at 0 DEG C, mixes with the trifluoroacetic acid of 1.92 ml (25.0 mmol), then at room temperature stir 1 hour.Mixture is desolvation and trifluoroacetic acid on rotatory evaporator.Crude product is in harmonious proportion in the toluene of 20 ml, again under reduced pressure concentrated on rotatory evaporator.Purify by the chromatography on silica gel.By with eluent ethyl acetate, separable go out nonpolar impurity.With methylene chloride/methanol/26% concentration ammonia solution (10:1:0.1) wash-out, obtain the target compound of 673 mg (theoretical value 79%).
LC-MS [method 3] R t=0.50 min; MS [ESIpos]: m/z=220 (M+H) +.
embodiment 91A
2-amino-2-[3-(trifluoromethyl) phenyl] ethanol trifluoroacetate
The compound of the embodiment 59A of 277mg (0.91 mmol) is dissolved in the methylene dichloride of 10 ml, then at 0 DEG C, mixes with the trifluoroacetic acid of 0.7 ml (9.1 mmol), then at room temperature stir 1 hour.Mixture is concentrated on rotatory evaporator.Crude product is in harmonious proportion in the toluene of 20 ml, again under reduced pressure concentrated on rotatory evaporator.Preparation property HPLC purification [method 19] for crude product.This obtains the target compound of 124 mg (theoretical value 43%).
LC-MS [method 5] R t=0.40 min; MS [ESIpos]: m/z=206 (M+H) +(free alkali)
1H-NMR (400 MHz, MeOD): δ = 3.82 (dd, 2H), 3.94 (dd, 1H), 4.49 (dd, 1H), 7.64-7.71 (m, 1H), 7.71-7.79 (m, 2H), 7.84 (s, 1H)。
embodiment 92A
2-amino-2-(2,3-difluorophenyl) ethylate hydrochlorate
Figure 740979DEST_PATH_IMAGE096
The compound of the embodiment 86A of 103 mg (0.38 mmol) is dissolved in the methylene dichloride of 2 ml, this solution at room temperature with 1.73 ml by hydrogenchloride two
Figure 446767DEST_PATH_IMAGE064
the 4M solution blending forming in alkane, then at room temperature stirs 2 hours.Mixture is concentrated on rotatory evaporator, and then residue is dry in HV.This obtains the target compound of 79 mg (theoretical value 100%).
LC-MS [method 4] R t=0.22 min; MS [ESIpos]: m/z=173 (M+H) +(free alkali).
embodiment 93A
(3RS)-3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-3-(2-fluorophenyl) propionic acid methyl ester
Figure 781933DEST_PATH_IMAGE097
The compound of the embodiment 8A of 50 mg (0.14 mmol) is dissolved in the DMF of 1 ml, with the EDC of 34 mg (0.18 mmol) and with the HOBt blending of 22 mg (0.16 mmol), then at room temperature stir 10 minutes.Then add 3-amino-3-(2-fluorophenyl) propionic acid methyl ester hydrochloride of 35 mg (0.15 mmol) and the triethylamine of 20 μ L (0.15 mmol), mixture at room temperature stirs 16 hours.For aftertreatment, the water blending of reaction mixture and 10 ml, then uses the ethyl acetate extracting twice of 10 ml.The organic phase dried over mgso merging, filters and concentrates on rotatory evaporator.Preparation property HPLC purification [method 19] for crude product.This obtains the target compound of 47 mg (theoretical value 63%).
LC-MS [method 3] R t=1.22 min; MS [ESIpos]: m/z=545 (M+H) +
1h-NMR (400 MHz, CDCl 3): δ=2.80-2.96 (m, 2H), 3.53 and 3.58 (2s, 3H), 3.93-4.12 (m, 2H), 4.44-4.82 (m, 3H), 5.05 (t, 1H), 5.56-5.67 (m, 1H), 6.98-7.24 (m, 3H), 7.27-7.37 (m, 2H), 7.47-7.64 (m, 3H), 7.70 (d, 2H).(part of the double signal group of non-enantiomer mixture splits.)。
Embodiment 94A
3-(4-chloro-phenyl-)-5-oxo-4-[(3, the fluoro-2-hydroxypropyl of 3,3-tri-] and-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetic acid
The compound of the embodiment 5A of 400 mg (1.05 mmol) reacts according to the mode identical with embodiment 8A.This obtains the title compound of 328 mg (theoretical value 85%).
LC/MS [method 6]: R t=2.01 min; M/z=366 (M+H) +.
Embodiment 95A
Amino [3-(trifluoromethyl) phenyl] acetic acid hydrochloride
Figure 402719DEST_PATH_IMAGE099
N-tert-butoxycarbonyl-2-(3-trifluoromethyl)-DL-glycine of consumption 1.00 g (3.13 mmol) and 15.7 ml by hydrogenchloride two
Figure 963013DEST_PATH_IMAGE064
4N solution in alkane mixes, and then at room temperature stirs a night.On rotatory evaporator, remove volatile constituent.Residue is dry in HV.This obtains the title compound of 795 mg (theoretical value 99%).
LC/MS [method 2]: R t=0.79 min; M/z=220 (M+H) +.
Embodiment 96A
2-(dibenzyl amino)-2-[3-(trifluoromethyl) phenyl] ethanol
Figure 469081DEST_PATH_IMAGE100
The solution that the bromotoluene of 1.48 ml (12.4 mmol) is formed in the ethanol of 5 ml is at room temperature added drop-wise in the initial soln that the compound (3.11 mmol) of the embodiment 95A of 795 mg and the salt of wormwood of 2.15 g (15.5 mmol) forms in the ethanol of 20 ml and the water of 5 ml.Gained mixture heats a night under refluxing.After being cooled to room temperature, on rotatory evaporator, remove desolventizing.The water blending of residue and 250 ml, is then extracted with ethyl acetate three times.The organic phase saturated sodium-chloride water solution washed twice merging, by dried over sodium sulfate, then concentrated on rotatory evaporator.(1.72 g) contain this residue, according to LC-MS (method 2), N, N-dibenzyl amino acid (Rt=2.66 minute), N, N-dibenzyl amino acid ethyl ester (Rt=3.21 minute) and N, the mixture of N-dibenzyl amino acid benzyl ester (Rt=3.32 minute).
This mixture is dissolved in the ether of 50 ml, then in argon atmosphere, adds in the 1M solution (12.9 ml, 12.9 mmol) being formed in THF by lithium aluminum hydride, it uses frozen water cooling subsequently.Then remove ice bath, reaction mixture heats 1 hour under refluxing.After being cooled to room temperature, excessive hydride decomposes with several dripping.Mixture stirs several minutes together with sodium sulfate, then filters.Filtrate is concentrated on rotatory evaporator.Dry in HV of residue obtains title compound (730 mg, theoretical value 28%).
LC/MS [method 2]: R t=2.72 min; M/z=386 (M+H) +
1h NMR (DMSO-d 6, 400 MHz): δ=7.59-7.70 (m, 4H), 7.29-7.38 (m, 8H), 7.20-7.26 (m, 2H), 4.69 (t, 1H), 3.94-4.05 (m, 2H), 3.72-3.82 (m, 3H), 3.30 (d, 1H) (possible 1H, under the water signal at 3.32 ppm places).
Embodiment 97A
2-(dibenzyl amino)-2-[3-(trifluoromethyl) phenyl] acetaldehyde
Figure 685299DEST_PATH_IMAGE101
The 2M solution of oxalyl dichloro in methylene dichloride with the methylene dichloride dilution of 10 ml, is then cooled to-78 DEG C in argon atmosphere.Solution by the DMSO of 221 μ L (3.11 mmol) in the methylene dichloride of 2 ml is added drop-wise to wherein.After 10 minutes, the solution of the compound of the embodiment 96A of 600 mg (1.56 mmol) in the methylene dichloride of 10 ml is dripped into.Mixture stirs 15 minutes at-78 DEG C, then with the triethylamine blending of 868 μ L (6.22 mmol).After other 10 minutes, remove cooling bath, mixture is warming up to room temperature, then mixes with the water of 20 ml and the methylene dichloride of 200 ml.Separate water, to purify.Organic phase washes with water twice and then with 5% concentration sodium bicarbonate aqueous solution washing, concentrates by dried over sodium sulfate with on rotatory evaporator.Residue is dry in HV.(600 mg quantitatively) further react as crude product title compound immediately.
LC/MS [method 6]: R t=3.18 min; M/z=384 (M+H) +.
Embodiment 98A
3-(dibenzyl amino)-1,1, the fluoro-3-[3-of 1-tri-(trifluoromethyl) phenyl] propane-2-alcohol
Figure 380853DEST_PATH_IMAGE102
The compound of the embodiment 97A of 300 mg (0.78 mmol) is dissolved in the THF of 5 ml, be cooled to 0 DEG C, then with (trifluoromethyl) trimethyl silane blending of 183 μ L (1.17 mmol), then the 1M solution in THF mixes with the tetra-n-butyl ammonium fluorochemical of 39 μ L (39 μ mol).Remove cooling bath, mixture at room temperature stirs a night.After the 1N of 2 ml hydrochloric acid adds, it stirs other 30 minutes.On rotatory evaporator, remove THF, product is purified by preparative chromatography (method 10).The title compound that this obtains 168 mg (theoretical value 47%), is non-enantiomer mixture (the about 3:2 of ratio)
LC/MS [method 4]: R t=1.43 min+1.45 min (ratio 3:2); M/z=454 in each situation (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 7.52-7.77 (m, 4H), 7.38-7.41 (m, 8H), 7.22-7.30 (m, 2H), 6.33 (d, 0.4 H Diast.1), 6.22 (d, 0.6H Diast.2), 4.97-5.09 (m, 0.6H Diast.2), 4.88-4.99 (0.4 H, Diast. 1), 4.03 (d, 0.8H, Diast.1), 3.97 (d, 1.2 H, Diast.2), 3.94 (d, 0.6H, Diast.2), 3.91 (d, 0.4H, Diast.1), 3.03 (d, 0.8H, Diast.1), 3.87 (d, 1.2H, Diast.2)。
Embodiment 99A
3-amino-1, the fluoro-3-[3-of 1,1-tri-(trifluoromethyl) phenyl] propane-2-alcohol
Figure 733337DEST_PATH_IMAGE103
At continuous flow hydrogenation apparatus (H-Cube, from Thales Nano, Budapest obtains, HC-2-SS type) in, the solution that the compound of the embodiment 98A of 168mg (0.37 mmol) forms in the methyl alcohol of 50 ml carries out hydrogenation (condition: Pd (OH) 2/ C box, the flow rate of 1 ml/min, RT, standard hydrogen atmospheric pressure).Reaction mixture is concentrated on rotatory evaporator, and residue is dry tout court in HV.Obtain title compound (93 mg, theoretical value 92%).
LC/MS [method 4]: R t=0.63 min+0.65 min (ratio 2:3); Each m/z=274 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 7.79 (s, 0.4H Diast.1), 7.76 (s, 0.6H Diast.2), 7.72 (d, 0.4H Diast.1), 7.67 (d, 0.6H Diast.2), 7.50-7.64 (m, 2H), 6.40 (br. d, 1H), 4.03-4.21 (m, 2H)。
Embodiment 100A
2-nitro-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester (non-racemic enantiomeric mixture)
Figure 738202DEST_PATH_IMAGE104
In argon atmosphere, the N of 9.75 ml (56 mmol), N-diisopropylethylamine is at room temperature added drop-wise in the suspension that the trifluoromethayl sulfonic acid zinc (II) of 20.35 g (56 mmol) forms in the Nitromethane 99Min. of 300 ml at leisure, and mixture stirs 1 hour.Yellow suspension subsequently with the (1R of 13.9 g (84 mmol), the molecular sieve of 2S)-(-)-2-(N-methylamino)-1-phenyl third-1-alcohol [(-)-N-methylephedrine] and 18.4 g mixes, then stir 1 hour, be then cooled to-20 DEG C.In dropping funnel, add the compound of the embodiment 11A of 51.0 g (186.6 mmol), add the Nitromethane 99Min. of 75 ml.Initial soln is spontaneously warming up to approximately 40 DEG C, and sedimentary formation starts to carry out.Afterwards, the entire content of dropping funnel is added in cooling trifluoromethayl sulfonic acid zinc (II)/(-)-N-methylephedrine mixture (there is no temperature control) as portion immediately.Reaction mixture stirs other 5 hours in cooling bath (20 DEG C), then stirs a night, and temperature is increased to-0 DEG C at leisure.Carry out similarly aftertreatment with the modification 1 of process.Crude product is by using short silica gel adsorption column (eluent methylene dichloride/ethanol 100:2) to purify.The fraction that contains product is merged, and on rotatory evaporator, except desolventizing, residue is dry in HV.Together with the Skellysolve A of the solid obtaining and 200 ml, at room temperature stir, again by filtering separation, and dry in HV.This obtains the title compound (have approximately 82% purity according to LC-MS, theoretical value 43%) of 32.4 g.
Wherein this product of 5 g is via HPLC[method 20] purify.This obtains the title compound of 3.87 g.
LC/MS [method 5]: R t=1.15 min; (ES neg.): m/z=333 (M-H) -.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.36 (s, 9H), 4.77 (dd, 1H), 4.97 (dd, 1H), 5.34-5.44 (m, 1H), 7.59-7.66 (m, 1H), 7.66-7.74 (m, 2H), 7.78 (br. s, 1H), 7.89 (br. d, 1H)。
Embodiment 101A
2-amino-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
(non-racemic enantiomeric mixture)
The compound of the embodiment 100A of 3.87 g (11.2 mmol) in the methyl alcohol of 230 ml with the Raney nickel suspension of 5 ml (in water 50%) hydrogenation 3 hours under the hydrogen pressure of 3 bar.Reaction mixture filters via Celite, then uses methanol wash, and this filtrate is removed desolventizing on rotatory evaporator.Residue is dry in HV.This obtains the title compound of 3.50 g (theoretical value 99%).
LC/MS [method 4]: R t=0.76 min; M/z=305 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.37 (s, 9H), 2.64-2.76 (m, 2H), 3.33 (s, 2H), 4.45-4.55 (m, 1H), 7.44 (br. d, 1H), 7.51-7.64 (m, 4H)。
Embodiment 102A
1-[3-(trifluoromethyl) phenyl] and ethane-1,2-bis-bases } the two carboxylamine tertiary butyl-methyl ester (non-racemic enantiomeric mixture)
Together with the triethylamine of the compound of the embodiment 101A of 500 mg (1.64 mmol) and 320 μ L (2.30 mmol), join in methylene dichloride, with ice-cooled, then add the methyl-chloroformate of 152 μ L (1.97 mmol).Remove ice bath, mixture stirs other 1 hour.On rotatory evaporator, remove desolventizing, preparation property HPLC[method 20 for residue] purify.Product fraction is merged, and on rotatory evaporator, except desolventizing, residue is dry in HV.This obtains the title compound of 428 mg (theoretical value 72%).
LC/MS [method 2]: R t=2.27 min; M/z=363 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.36 (s, 9H), 3.19-3.26 (m, 2H), 3.46 (br. s, 3H), 4.64-4.76 (m, 1H), 7.18 (br. t, 1H), 7.49 (br. d, 1H), 7.53-7.65 (m, 4H)。
Embodiment 103A
1-[3-(trifluoromethyl) phenyl] and ethane-1,2-bis-bases } the two carboxylamine tertiary butyl-ethyl esters (non-racemic enantiomeric mixture)
Figure 882373DEST_PATH_IMAGE107
The solution of the triethylamine of the compound of the embodiment 101A of 500 mg (1.64 mmol) and 321 μ L (2.30 mmol) in the methylene dichloride of 15 ml is cooled to 0 DEG C, then mixes with the Vinyl chloroformate of 189 μ L (1.97 mmol).Remove ice bath, mixture stirs other 1 hour.On rotatory evaporator, remove volatile component, preparation property HPLC[method 20 for residue] purify.Product fraction is merged, then on rotatory evaporator, removes desolventizing.Residue is dry in HV.This obtains the title compound of 527 mg (theoretical value 85%).
LC/MS [method 2]: R t=2.37 min; M/z=377 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.08 (t, 3H), 1.35 (s, 9H), 3.18-3.27 (m, 2H), 3.85-3.97 (m, 2H), 4.65-4.77 (m, 1H), 7.13 (br. t, 1H), 7.48 (br. d, 1H), 7.52-7.64 (m, 4H)。
Embodiment 104A
2-[(ethylamino formyl radical) and amino]-1-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (non-racemic enantiomeric mixture)
The solution of the compound of the embodiment 101A of 500 mg (1.64 mmol) in the methylene dichloride of 15 ml mixes with the ethyl isocyanate of 260 μ L (3.29 mmol) at 0 DEG C.Remove ice bath, reaction mixture stirs other 1 hour.Then, on rotatory evaporator, removing whole volatile components.Preparation property HPLC[method 23 for residue] purify.Product fraction desolvation on rotatory evaporator.In HV, residue dry obtains the title compound of 546 mg (theoretical value 89%).
LC/MS [method 2]: R t=2.16 min; M/z=376 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 0.95 (t, 3H), 1.35 (s, 9H), 2.91-3.04 (m, 2H), 3.08-3.19 (m, 1H), 3.21-3.31 (m, 1H), 4.57-4.66 (m, 1H), 5.88 (br. t, 1H), 5.96 (br. t, 1H), 7.48-7.64 (m, 5H)。
Embodiment 105A
1-[3-(trifluoromethyl) phenyl] and ethane-1,2-bis-bases } two carboxylamine 2-bromotrifluoromethane-tertiary butyl ester (non-racemic enantiomeric mixture)
Figure 717791DEST_PATH_IMAGE109
The solution that the DIPEA of the compound of the embodiment 101A of 272 mg (0.89 mmol) and 171 μ L (0.98 mmol) forms in the acetonitrile of 3 ml carries out blending by drip the solution being formed by the chloroformic acid 2-bromo-ethyl ester of 106 μ L (0.98 mmol) in the acetonitrile of 2 ml.For aftertreatment, after 10 minutes, add ethyl acetate and saturated sodium bicarbonate aqueous solution.Organic phase is separated, again, with saturated sodium bicarbonate aqueous solution washing, by dried over sodium sulfate, and on rotatory evaporator, removes volatile component.In HV, residue dry obtains the title compound of 352 mg (theoretical value 82%).
LC/MS [method 4]: R t=1.15 min; M/z=455/457 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.36 (s, 9H), 3.25 (t, 2H), 3.56 (t, 2H), 4.09-4.28 (m, 2H), 4.66-4.79 (m, 1H), 7.39 (br. t, 1H), 7.45-7.69 (m, 5H)。
Embodiment 106A
{ 2-(2-oxo-1,3-
Figure 942099DEST_PATH_IMAGE064
azoles alkane-3-yl)-1-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine tertiary butyl ester (non-racemic enantiomeric mixture)
Figure 85154DEST_PATH_IMAGE110
The solution of the compound of the embodiment 105A of 352 mg (0.77 mmol) in the DMF of 10 ml and the sodium hydride of 34 mg (0.85 mmol) (in mineral oil 60%) blending.Reaction mixture at room temperature stirs a night.In order to purify, add the 1N hydrochloric acid of 2 ml, preparation property HPLC[method 23 for whole mixture] purify.Product fraction is merged, then on rotatory evaporator, removes desolventizing.Dry in HV of residue obtains the title compound of 242 mg (theoretical value 84%).
LC/MS [method 3]: R t=1.19 min; M/z=275 (M+H-BOC) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.37 (s, 9H), 3.34-3.44 (m, 2H), 3.45-3.62 (m, 2H), 4.12-4.23 (m, 2H), 4.85-4.95 (m, 1H), 7.55-7.66 (m, 3H), 7.69 (d, 1H), 7.78 (br. s., 1H)。
Embodiment 107A
2-(2-oxo-imidazole alkane-1-yl)-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester (non-racemic enantiomeric mixture)
The ice-cooled solution of the compound of the embodiment 101A of 302 mg (0.99 mmol) in the methylene dichloride of 10 ml mixes by the 2-bromotrifluoromethane isocyanic ester that drips 99 μ L (1.09 mmol).After 10 minutes, remove ice bath, mixture stirs other 5 minutes.On rotatory evaporator, remove whole volatile constituents.Residue is blended in the anhydrous THF of 5 ml, then using ice-cooled in the situation that, with sodium hydride (60%, 1.09 mmol in the mineral oil) blending of 44 mg.After 2 hours, add the 1M hydrochloric acid of 1 ml, reaction mixture is desolvation on rotatory evaporator.Water-based residue is dissolved in DMSO, then by preparation property HPLC[method 23] purify.Product fraction desolvation on rotatory evaporator.Dry in HV of residue obtains the title compound of 210 mg (theoretical value 38%).
LC/MS [method 4]: Rt=0.84+0.99 min; M/z=374 (M+H)+.
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (br. s., 9H), 3.09-3.18 (m, 2H), 3.18-3.32 (m, 4H), 4.74-4.86 (m, 1H), 6.25-6.39 (br. s, 1H), 7.44-7.76 (m, 5H)。
Embodiment 108A
2-(methylsulfinyl)-1-[2-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester (racemic non-enantiomer mixture)
Figure 782031DEST_PATH_IMAGE112
The solution that the dimethyl sulfoxide (DMSO) of 780 μ L (11.0 mmol) forms in the THF of 30 ml mixes by the n-butyllithium solution (1.6M in hexane, 11.0 mmol) that adds lentamente 6.9 ml at-78 DEG C.Gained suspension stirs 30 minutes at-78 DEG C, then adds among the solution (being cooled in advance-78 DEG C) being formed in the THF of 30 ml by the compound of the embodiment 15A of 1g (3.66 mmol).Reaction mixture stirs 30 minutes at-78 DEG C again, is then warming up at leisure room temperature.After at room temperature 30 minutes, it is cooled to-20 DEG C again, carrys out stopped reaction by the 10% concentration aqueous ammonium chloride solution that adds 20 ml.Mixture dilutes by ethyl acetate.Organic phase is separated, washes with water twice and washs once with saturated sodium-chloride water solution, removes volatile component by dried over sodium sulfate with on rotatory evaporator.Preparation property HPLC[method 20 for residue] purify.Product fraction desolvation on rotatory evaporator.Dry in HV of residue obtains the title compound of 952 mg (theoretical value 74%), is non-enantiomer mixture.
LC/MS [method 5]: R t=0.92+0.95 min; M/z=352 (M+H) +.
Embodiment 109A
2-(methylthio group)-1-[2-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester (racemoid)
Figure 606768DEST_PATH_IMAGE113
By the compound of the embodiment 108A of 400 mg (1.14 mmol), and the triphenylphosphine of 567 mg (2.16 mmol), be dissolved in the tetrachloromethane of 14 ml.Reaction mixture stirs a night under reflux temperature, then on rotatory evaporator, removes desolventizing.Preparation property HPLC[method 20 for residue] purify.Product fraction desolvation on rotatory evaporator.The dry title compound that obtains 340 mg (theoretical value 85%) in HV.
LC/MS [method 4]: Rt=1.20 min; M/z=336 (M+H) +.
1H-NMR (400 MHz, DMSO-d6): δ = 1.36 (s, 9H), 2.08 (s, 3H), 2.62 (dd, 1H), 2.71 (dd, 1H), 5.04-5.14 (m, 1H), 7.47 (t, 1H), 7.58 (br. d, 1H), 7.64-7.72 (m, 2H), 7.76 (br. d, 1H)。
Embodiment 110A
[(2-chloro-phenyl-) (phenyl sulfonyl) methyl] carboxylamine tertiary butyl ester
Figure 788351DEST_PATH_IMAGE114
The benzene sulfinic acid acid sodium-salt of the carboxylamine tertiary butyl ester of consumption 2.78 g (23.7 mmol) and 7.79 g (47.4 mmol) is at room temperature introduced in the methanol/water (1:2) of 55 ml, then mix with the 2-chlorobenzaldehyde of 5 g (35.6 mmol), then mix with the formic acid of 1.78 ml (47.1 mmol).Mixture at room temperature stirs 2 days.The white solid of precipitation obtains the each washed twice of water and ether in succession through suction filtration.The dry title compound that obtains 5.77 g (theoretical value 42%) in HV.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.21 (s, 9H), 6.54 (d, 1H), 7.42-7.58 (m, 3H), 7.62-7.70 (m, 2H), 7.73-7.79 (m, 1H), 7.82 (d, 2H), 7.92-8.03 (m, 1H), 8.87 (d, 1H)。
Embodiment 111A
[(E)-(2-chloro-phenyl-) methylene radical] carboxylamine tertiary butyl ester
Figure 56652DEST_PATH_IMAGE115
The salt of wormwood of consumption 12.53 g (90.7 mmol) heats in HV, then cooling in argon atmospher.The compound that adds the anhydrous THF of consumption 140 ml and the embodiment 110A of 5.77 g (15.1 mmol), mixture stirs 16 hours in argon atmospher under reflux temperature.After being cooled to room temperature, reaction mixture filters via Celite.Solid washs with a small amount of THF.Whole filtrate desolvation on rotatory evaporator.Oiliness residue is dry in HV.This obtains the title compound of 3.55 g (theoretical value 98%).
1H-NMR (400 MHz, DMSO-d 6): δ = 1.52 (s, 9H), 7.47-7.53 (m, 1H), 7.61-7.69 (m, 2H), 8.05 (d, 1H), 9.10 (s, 1H)。
Embodiment 112A
[1-(2-chloro-phenyl-)-2-nitro-ethyl] carboxylamine tertiary butyl ester (racemoid)
Figure 956475DEST_PATH_IMAGE116
The Nitromethane 99Min. of consumption 16 ml (295.41 mmol) mixes with the DIPEA of 436 μ L (2.50 mmol), and this yellow solution at room temperature stirs 1 hour.Then the compound that adds the embodiment 111A of 2.0 g (8.34 mmol), mixture at room temperature stirs a night.Whole volatile components are removed on rotatory evaporator.The in the situation that of boiling heating, residue is dissolved in the Virahol of 9 ml, then solution be cooled to 0 DEG C.The white solid of precipitation obtains by suction filtration, then with a small amount of cold isopropanol washing.The dry title compound that obtains 1.18 g (theoretical value 47%) in HV.
Mother liquor is under reduced pressure concentrated, preparation property HPLC[method 23 for residue] purify.Product fraction desolvation on rotatory evaporator, then dry in HV.This obtains the title compound of other 0.90 g (theoretical value 36%).
LC/MS [method 2]: R t=2.30 min; M/z=301 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.35 (s, 9H), 4.62 (dd, 1H), 4.81 (dd, 1H), 5.73 (dt, 1H), 7.32-7.44 (m, 2H), 7.49 (dd, 1H), 7.54 (dd, 1H), 8.00 (d, 1H)。
Embodiment 113A
[2-amino-1-(2-chloro-phenyl-) ethyl] carboxylamine tertiary butyl ester
According to the mode identical with embodiment 33A, obtain title compound: 993 mg (quantitatively) from the compound of the embodiment 112A of 1.0g (3.33 mmol).
LC/MS [method 4]: R t=0.68 min; M/z=271 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.36 (s, 9H), 1.65 (br. s., 2H), 2.58 (dd, 1H), 2.72 (dd, 1H), 4.79-4.87 (m, 1H), 7.24 (dt, 1H), 7.32 (t, 1H), 7.35-7.40 (m, 2H), 7.45 (br. d, 1H)。
Embodiment 114A
[2-(carbamido group)-1-(2-chloro-phenyl-) ethyl] carboxylamine tertiary butyl ester
The solution of the compound of the embodiment 113A of 330 mg (1.15 mmol) in water/methyl alcohol (1:1) of 12 ml at room temperature mixes with the potassium cyanate of 279 mg (3.44 mmol).Mixture heats 1 hour at 40 DEG C, then mixes with the 1M hydrochloric acid (1.15 mmol) of 1.15 ml and at room temperature stirs a night.Add the potassium cyanate of other 93 mg (1.14 mmol), mixture at room temperature further stirs 3 hours.Preparation property HPLC[method 10 for whole reaction mixture] purify.Product fraction desolvation on rotatory evaporator.Dry in HV of residue obtains the title compound of 292 mg (theoretical value 80%).
LC/MS [method 4]: R t=0.86 min; M/z=314 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.35 (s, 9H), 3.03-3.13 (m, 1H), 3.19-3.29 (m, 1H), 4.84-4.94 (m, 1H), 5.56 (br. s, 2H), 6.01-6.08 (m, 1H), 7.26 (dt, 1H), 7.33 (t, 1H), 7.37-7.43 (m, 2H), 7.52 (br. d, 1H)。
Embodiment 115A
1-(2-chloro-phenyl-)-2-[(methyl sulphonyl) and amino] ethyl } carboxylamine tertiary butyl ester
Figure 60194DEST_PATH_IMAGE119
The solution of the compound of the embodiment 113A of 330mg (1.15 mmol) in the pyridine of 7 ml at room temperature mixes with the methylsulfonyl chloride of 177 μ L (2.29 mmol).After 1 hour, on rotatory evaporator, remove volatile component.Preparation property HPLC[method 23 for residue] purify.Product fraction desolvation on rotatory evaporator.Dry in HV of residue obtains the title compound of 312 mg (theoretical value 78%).
LC/MS [method 4]: R t=0.96 min; M/z=349 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.37 (s, 9H), 2.82 (s, 3H), 3.08 (ddd, 1H), 3.14-3.23 (m, 1H), 5.01-5.10 (m, 1H), 7.21 (t, 1H), 7.29 (dt, 1H), 7.35 (br. t, 1H), 7.41 (dd, 1H), 7.44 (br. d, 1H), 7.50 (dd, 1H)。
Embodiment 116A
1-(2-chloro-phenyl-)-2-[(ethylsulfonyl) and amino] ethyl } carboxylamine tertiary butyl ester
According to the mode identical with embodiment 115A, from the compound of embodiment 113A and the ethanesulfonyl chloride of 217 μ L (2.29 mmol) of 330 mg (1.15 mmol), obtain the title compound of 263 mg (theoretical value 63%).
LC/MS [method 4]: R t=1.01 min; M/z=363 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.14 (t, 3H), 1.37 (s, 9H), 2.84-3.00 (m, 2H), 3.07 (ddd, 1H), 3.12-3.22 (m, 1H), 4.99-5.08 (m, 1H), 7.23-7.31 (m, 2H), 7.32-7.38 (m, 1H), 7.41 (dd, 1H), 7.42 (br. d, 1H), 7.49 (dd, 1H)。
Embodiment 117A
[1-(2-chloro-phenyl-)-2-(methyl sulphonyl) ethyl] carboxylamine tertiary butyl ester
Figure 613852DEST_PATH_IMAGE121
The solution that (methyl sulphonyl) methane of 1 g (10.6 mmol) forms in the THF of 30 ml is cooled to-78 DEG C; then the n-butyllithium solution (1.6M in hexane, 10.6 mmol) that adds at leisure 6.65 ml mixes.At-78 DEG C after 30 minutes, the suspension obtaining is added among the solution (being cooled in advance-78 DEG C) that the compound of the embodiment 111A of 850 mg (3.55 mmol) forms in the THF of 20 ml.Reaction mixture stirs 30 minutes at-78 DEG C, is then warming up at leisure room temperature.After 30 minutes, it is cooled to-20 DEG C again, carrys out stopped reaction by the 10% concentration aqueous ammonium chloride solution that adds 20 ml.Mixture dilutes by ethyl acetate.Organic phase is separated, washes with water twice and washs once with saturated sodium-chloride water solution.Organic phase dried over sodium sulfate, filters and removes on rotatory evaporator desolventizing.Together with the methanol/water (10:1) of residue and 10 ml, stir, suction filtration goes out solids.Together with pentane/Virahol 5:1 of lurid solid and 20 ml, stir, and then suction filtration.The dry title compound (82% purity, according to LC/MS) that obtains 800 mg (theoretical value 55%) in HV.
LC/MS [method 3]: R t=1.08 min; M/z=234 (M+H-BOC) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.36 (s, 9H), 3.01 (s, 3H), 3.19-3.28 (m, 1H), 3.43-3.55 (m, 1H), 5.47-5.54 (m, 1H), 7.28-7.35 (m, 1H), 7.38 (t, 1H), 7.45 (d, 1H), 7.51 (d, 1H), 7.82 (br. d, 1H)。
Embodiment 118A
[1-(2-chloro-phenyl-)-2-(methylsulfinyl) ethyl] carboxylamine tertiary butyl ester
(racemic non-enantiomer mixture)
Figure 770027DEST_PATH_IMAGE122
According to the mode identical with embodiment 108A, obtain title compound from the compound of the embodiment 111A of 850 mg (3.55 mmol): 697 mg (theoretical value 62%).
LC/MS [method 4]: R t=0.87+0.88 min; M/z=318 (M+H) +.
1h-NMR (400 MHz, DMSO-d 6): δ=1.36 (s, 9H), 2.55 (br. s., " 1.5 H " (3H the first diastereomer)), 2.64 (s, " 1.5 H " (3H the second diastereomers)), 2.81-3.15 (m, 2H), 5.22-5.38 (m, 1H), 7.31 (br. t, 1H), 7.35-7.50 (m, 3H), 7.54 (br. d, 1H), 7.75-7.87 (m, 1H).
Embodiment 119A
[1-(2-chloro-phenyl-)-2-(methylthio group) ethyl] carboxylamine tertiary butyl ester (racemoid)
Figure 380131DEST_PATH_IMAGE123
According to the mode identical with embodiment 109A, the compound of the embodiment 118A of 100 mg (0.32 mmol) is reduced.This obtains the title compound of 44 mg (theoretical value 45%).
LC/MS [method 5]: R t=1.20 min; M/z=302 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.37 (s, 9H), 2.11 (s, 3H), 2.59-2.72 (m, 2H), 5.05-5.17 (m, 1H), 7.27 (dt, 1H), 7.35 (t, 1H), 7.41 (dd, 1H), 7.49 (dd, 1H), 7.57 (br. d, 1H)。
Embodiment 120A
2-(methyl sulphonyl)-1-[2-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
According to the mode identical with embodiment 117A, obtain the title compound of 1.11 g (theoretical value 82%) from the compound of (methyl sulphonyl) methane of 1.03 g (11.0 mmol) and the embodiment 15A of 1.0 g (3.7 mmol).
LC/MS [method 3]: R t=1.12 min; M/z=268 (M+H-BOC) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.35 (s, 9H), 2.99 (s, 3H), 3.19 (br. d, 1H), 3.58 (dd, 1H), 5.53 (br. t, 1H), 7.50 (t, 1H), 7.67-7.80 (m, 3H), 7.85 (br. d, 1H)。
Embodiment 121A
2-(methyl sulphonyl)-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 224776DEST_PATH_IMAGE125
By using the method identical with embodiment 117A, obtain the title compound of 535 mg (theoretical value 27%) from the compound of (methyl sulphonyl) methane of 1.50 g (15.9 mmol) and the embodiment 11A of 1.45 g (5.31 mmol).
LC/MS [method 4]: R t=1.02 min; M/z=368 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.36 (s, 9H), 2.99 (s, 3H), 3.48-3.64 (m, 2H), 5.17 (m, 1H), 7.56-7.70 (m, 3H), 7.70-7.78 (m, 2H)。
Embodiment 122A
2-(dimethylamino-sulfonyl)-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 235458DEST_PATH_IMAGE126
The N of 676 mg (5.49 mmol), the solution that N-dimethyl methyl sulphonamide forms in the THF of 10 ml carries out blending by the 1.6M n-Butyl Lithium hexane solution that adds lentamente 3.43 ml (5.49 mmol) at-78 DEG C.At-78 DEG C after 30 minutes, among the solution (being cooled in advance-78 DEG C) of the compound of embodiment 11A that the colourless solution obtaining is added to 500 mg (1.83 mmol) in the THF of 10 ml.Reaction mixture stirs 30 minutes at-78 DEG C again, is then warming up at leisure room temperature.After 30 minutes, it is cooled to-20 DEG C again, carrys out stopped reaction by the 10% concentration aqueous ammonium chloride solution that adds 5 ml.Mixture dilutes by ethyl acetate, then washes with water twice and washs once with saturated sodium-chloride water solution.Organic phase dried over sodium sulfate is then removed desolventizing on rotatory evaporator.Preparation property HPLC[method 23 for residue] purify.Product fraction desolvation on rotatory evaporator.Dry in HV of residue obtains the title compound of 296 mg (theoretical value 41%).
LC/MS [method 3]: R t=1.28 min; M/z=297 (M+H-BOC) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.36 (s, 9H), 2.76 (s, 6H), 3.33 (dd, 1H), 3.53 (dd, 1H), 5.01-5.11 (m, 1H), 7.56-7.69 (m, 4H), 7.71 (br. s, 1H)。
Embodiment 123A
[1-(2,3-dichlorophenyl) ethane-1,2-bis-bases] the two carboxylamine tertiary butyl-methyl ester
Figure 203414DEST_PATH_IMAGE127
The solution of the compound of the embodiment 40A of 192mg (0.63 mmol) in the methylene dichloride of 5.7 ml at room temperature mixes with the triethylamine of 123 μ L (0.88 mmol) together and then mixes with the methyl-chloroformate of 58 μ L (0.75 mmol).Reaction mixture at room temperature stirs a night, then on rotatory evaporator, removes whole volatile components.Residue is dissolved in DMSO, then by preparation property HPLC[method 20] purify.Product fraction desolvation on rotatory evaporator, then dry in HV.This obtains the title compound of 167 mg (theoretical value 73%).
LC/MS [method 3]: R t=1.22 min; M/z=263 (M+H-BOC) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 3.14-3.27 (m, 2H), 3.48 (s, 3H), 5.07 (br. q, 1H), 7.13-7.21 (m, 1H), 7.32-7.38 (m, 1H), 7.38-7.44 (m, 1H), 7.47 (br. d, 1H), 7.53 (dd, 1H)。
Embodiment 124A
[1-(2,3-dichlorophenyl) ethane-1,2-bis-bases] the two carboxylamine tertiary butyl-ethyl esters
Figure 109665DEST_PATH_IMAGE128
According to the mode identical with embodiment 123A, prepare the title compound of 184 mg (theoretical value 78%) from the compound of embodiment 40A of 192 mg (629 μ mol) and the Vinyl chloroformate of 72 μ L (755 μ mol).
LC/MS [method 3]: R t=1.29 min; ES +: m/z=277 (M+H-BOC) +.ES -: m/z = 375 (M-H) -
1H-NMR (400 MHz, DMSO-d 6): δ = 7.31-7.57 (m, 4H), 7.12 (br. t., 1H), 5.07 (q, 1H), 3.88-3.98 (m, 2H), 3.12-3.28 (m, 2H), 1.35 (m, 9H), 1.10 (t, 3H)。
Embodiment 125A
[2-(carbamido group)-1-(2,3-dichlorophenyl) ethyl] carboxylamine tertiary butyl ester
Figure 555690DEST_PATH_IMAGE129
The compound of the embodiment 40A of 192 mg (0.63 mmol) is introduced in water/methyl alcohol 1:2 of 11 ml, then at room temperature in succession with the potassium cyanate blending of 1M hydrochloric acid and 166 mg (2.05 mmol) of 0.63 ml (0.63 mmol).Reaction mixture at room temperature stirs a night, then methanol removal on rotatory evaporator.Residue is dissolved in DMSO, then by preparation property HPLC[method 20] purify.Product fraction is concentrated on rotatory evaporator.Dry in HV of residue obtains the title compound of 177 mg (theoretical value 73%).
LC/MS [method 3]: R t=1.05 min; M/z=348 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.34 (s, 9H), 3.04-3.19 (m, 1H), 3.19-3.30 (m, 1H), 4.86-4.99 (m, 1H), 5.57 (br. s., 2H), 6.02-6.16 (br.m, 1H), 7.31-7.42 (m, 2H), 7.47-7.57 (m, 1H), 7.61 (d, 1H)。
Embodiment 126A
1-(2,3-dichlorophenyl)-2-[(ethylamino formyl radical) and amino] ethyl } carboxylamine tertiary butyl ester
The solution of the compound of the embodiment 40A of 192 mg (0.63 mmol) in the methylene dichloride of 5.7 ml at room temperature mixes with the ethyl isocyanate of 100 μ L (1.26 mmol).Reaction mixture at room temperature stirs a night, then on rotatory evaporator, removes desolventizing.Residue is dissolved in DMSO, then by preparation property HPLC[method 20] purify.Product fraction desolvation on rotatory evaporator.Dry in HV of residue obtains the title compound of 173 mg (theoretical value 73%).
LC/MS [method 3]: R t=1.16 min; M/z=276 (M+H-BOC) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 0.96 (t, 3H), 1.34 (s, 9H), 2.89-3.07 (m, 2H), 3.07-3.19 (m, 1H), 3.23-3.32 (m, 2H), 4.88-4.99 (m, 1H), 5.88-6.01 (m, 2H), 7.31-7.43 (m, 2H), 7.48-7.56 (m, 1H), 7.60 (br. d, 1H)。
Embodiment 127A
3-amino-3-[3-(trifluoromethyl) phenyl] propane-1-alcohol
Figure 887631DEST_PATH_IMAGE131
With ice-cooled and in argon gas, introduce borine-tetrahydrofuran (THF) title complex (1M in THF) of 10.9 ml (10.94 mmol).Then add 3-amino-3-[3-(trifluoromethyl) phenyl of 850 mg (3.65 mmol)] propionic acid.After 5 minutes, remove cooling bath, mixture at room temperature stirs a night and stirs 4 hours under refluxing.After being cooled to room temperature, add several flake ices, until gas is emitted end.Mixture is adjusted to alkalescence with 1M aqueous sodium hydroxide solution, is diluted with water to the volume of approximately 150 ml, then uses dichloromethane extraction three times.The organic phase dried over sodium sulfate merging, filters and removes on rotatory evaporator desolventizing.The dry title compound that obtains 744 mg (theoretical value 85%) in HV, 92% purity.
LC/MS [method 4]: R t=0.45 min; M/z=220 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 7.71 (s, 1H), 7.60-7.67 (m, 1H), 7.49-7.58 (m, 2H), 4.55 (br.s, 1H), 3.97-4.04 (dd, 1H), 3.34-3.50 (m, 2H), 2.00 (br. s., 2H), 1.59-1.78 (m, 2H)。
Embodiment 128A
3-hydroxyl-1-[3-(trifluoromethyl) phenyl] and propyl group } carboxylamine tertiary butyl ester
Figure 284109DEST_PATH_IMAGE132
The solution of the compound of the embodiment 127A of 744 mg (3.39 mmol) in the methylene dichloride of 30 ml mixes with the heavy carbonic di-t-butyl ester of 1.56 ml (6.79 mmol), at room temperature stirs 3 hours.For aftertreatment, the ethyl acetate dilution of 100 ml for reaction mixture, then by succession using 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washed twice separately.Organic phase dried over sodium sulfate is then removed desolventizing on rotatory evaporator.Preparation property HPLC[method 23 for residue] purify.Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 870 mg (theoretical value 80%).
LC/MS [method 5]: R t=1.03 min; M/z=320 (M+H) +.
1h-NMR (400 MHz, DMSO-d 6) (main rotational isomer): δ=7.52-7.67 (m, 4H), 7.49 (d, 1H), 4.70 (q, 1H), 4.53 (t, 1H), 3.35-3.45 (m, 1H), 3.23-3.30 (m, 1H), 1.79-1.90 (m, 1H), 1.64-1.78 (m, 1H), 1.44 (s, 9H).
Embodiment 129A
Carboxylamine 3-amino-3-[3-(trifluoromethyl) phenyl] propyl diester
Figure 533824DEST_PATH_IMAGE133
The compound of the embodiment 128A of 827 mg (2.59 mmol) is joined in the acetonitrile of 100 ml.What the chloro sulfonyl isocyanate of 676 μ L (7.77 mmol) formed in the acetonitrile of 10 ml is dripped at-15 DEG C.After 5 minutes, add the water of 50 ml, mixture heats a night at 60 DEG C.Reaction mixture mixes with saturated sodium bicarbonate aqueous solution, is then extracted with ethyl acetate three times.The organic phase dried over sodium sulfate merging is then removed desolventizing on rotatory evaporator.The dry title compound that obtain 678 mgs (quantitatively) of residue in HV.
LC/MS [method 2]: R t=1.06 min; M/z=263 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 7.72 (s, 1H), 7.64 (d, 1H), 7.51-7.61 (m, 2H), 6.43 (br. s, 2H), 3.90-4.01 (m, 2H), 3.82 (dt, 1H), 3.30 (s, 2H), 1.73-1.93 (m, 2H)。
Embodiment 130A
Amino [3-(difluoromethyl) phenyl] acetic acid ethyl ester
Figure 519098DEST_PATH_IMAGE134
3-(difluoromethyl) phenyl-bromide of consumption 1.0 g (4.83 mmol), N-(phenylbenzene methylene radical) the glycine ethyl ester of 1.42 g (5.31 mmol), the 1M solution of the tri-butyl phosphine of 0.19 ml (0.193 mmol) in toluene, two (two benzal benzylacetones) palladiums (0) of 55 mg (0.10 mmol), the 3M hydrochloric acid of the potassiumphosphate of 3.08 g (14.49 mmol) and 6.04 ml (18.11 mmol) is heated to 100 DEG C in argon gas in the degassed toluene of 20 ml, and stirs a night at this temperature.Add the tri-butyl phosphine (1M solution in toluene) of other 0.19 ml (0.193 mmol) and two (two benzal benzylacetones) palladiums (0) of 55 mg (0.10 mmol), mixture stirs other 24 hours at 100 DEG C.Mixture is cooled to room temperature, filters by Celite.The a small amount of toluene wash of this Celite, filtrate is under reduced pressure except desolventizing.For the cancellation of blocking group, residue is dissolved in the acetonitrile neutralization of 50 ml and the 3M mixed in hydrochloric acid of 15 ml.After 2 hours, on rotatory evaporator, remove acetonitrile fraction.Water-based residue is diluted with water to the volume of approximately 150 ml, then with ether washing three times.Water, by using 2M aqueous sodium carbonate to be adjusted to 9 pH value, is then used dichloromethane extraction three times.The organic phase dried over sodium sulfate merging, filters and removes on rotatory evaporator desolventizing.The dry title compound that obtains 265 mg (theoretical value 6.46%) in HV, approximately 27% purity, its further reaction in the situation that not purifying in addition.
LC/MS [method 3]: R t=0.63 min; M/z=230 (M+H) +.
Embodiment 131A
[(tert-butoxycarbonyl) amino] [3-(difluoromethyl) phenyl] acetic acid ethyl ester
Figure 891173DEST_PATH_IMAGE135
Together with the heavy carbonic di-t-butyl ester of the compound of the embodiment 130A of 265 mg (1.16 mmol) and 505 mg (2.31 mmol), in the methylene dichloride of 10.2 ml, at room temperature stir 3 hours.Then on rotatory evaporator, remove desolventizing.Preparation property HPLC purification for residue [method 20, and again by method 23].Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains 62 mg (theoretical value 29%), approximately 49% purity.
LC/MS [method 2]: R t=2.42 min; M/z=330 (M+H) +.
Embodiment 132A
1-[3-(difluoromethyl) phenyl] and-2-hydroxyethyl } carboxylamine tertiary butyl ester
Figure 961898DEST_PATH_IMAGE136
At room temperature, together with the lithium chloride of 11.97 mg (0.28 mmol) and the sodium borohydride of 10.68 mg (0.28 mmol), in the ethanol of 0.25 ml, stir 15 minutes.Then mixture is cooled to 0 DEG C, then drips the solution being formed in the tetrahydrofuran (THF) of 0.25 ml by the compound of the embodiment 131A of 62 mg (approximately 0.09 mmol, purity 49%).Mixture at room temperature stirs a night.For aftertreatment, it,, with ice-water cooling, then uses 1M hydrochloric acid to be adjusted to pH 2.Preparation property HPLC[method 20 for reaction mixture] purify.Product fraction desolvation on rotatory evaporator, then dry in HV.This obtains the title compound of 56 mg (approximately 45% purity, theoretical value 93%).
1H-NMR (400 MHz, DMSO-d 6): δ = 1.36 (br. s, 9H), 3.45-3.56 (m, 2H), 4.49-4.64 (m, 1H), 4.82 (t, 1H), 7.01 (t, J H-F = 56 Hz, 1H), 7.18-7.53 (m, 4H)。
Embodiment 133A
(2-[(tert-butoxycarbonyl) and amino]-2-[3-(trifluoromethyl) phenyl] ethyl } amino-sulfonyl) carboxylamine tertiary butyl ester
Figure 828354DEST_PATH_IMAGE137
The solution of the trimethyl carbinol of 110 mg (1.48 mmol) in the methylene dichloride of 2 ml is cooled to 0 DEG C, and the solution of the chloro sulfonyl isocyanate that then drips 129 μ L (1.48 mmol) in the methylene dichloride of 2 ml mixes.Mixture at room temperature stirs 1 hour.In syringe, draw the solution of 820 μ L, in the solution of the compound of embodiment 22A that is then added drop-wise to 90 mg (296 μ mol) in the methylene dichloride of 2 ml.Then add the DIPEA of 103 μ L, reaction mixture at room temperature stirs other 2 hours.On rotatory evaporator, remove volatile component.Residue is dissolved in a small amount of acetonitrile, then with the 1M hydrochloric acid blending of 1 ml, and preparation property HPLC[method 23 for the solution obtaining] purify.Containing fraction desolvation on rotatory evaporator of product, residue is dry in HV.This obtains the title compound of 111 mg (theoretical value 76%).
LC/MS [method 5]: R t=1.16 min; M/z=484 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.36 (s, 9H), 1.41 (s, 9H), 3.08-3.23 (m, 2H), 4.70-4.82 (m, 1H), 7.50 (br. d, 1H), 7.54-7.72 (m, 5H), 10.91 (br. s, 1H)。
Embodiment 134A
N-{2-amino-2-[3-(trifluoromethyl) phenyl] ethyl } sulfonic acid diamine
Figure 668134DEST_PATH_IMAGE138
The hydrogenchloride of the solution of the compound of the embodiment 133A of 100 mg (0.20 mmol) in the methylene dichloride of 2 ml and 2 ml is two
Figure 148794DEST_PATH_IMAGE064
4M solution blending in alkane, mixture at room temperature stirs 2 hours.It dilutes by ethyl acetate, then mixes with 10% concentration sodium bicarbonate aqueous solution.Alkalescence water is extracted with ethyl acetate twice.The organic phase dried over sodium sulfate merging is then removed desolventizing on rotatory evaporator.Residue is title compound (53 mg, theoretical value 92%).
1H-NMR (400 MHz, DMSO-d 6): δ = ca. 2.66 (br. s, 2H), 2.86-2.99 (m, 1H), 2.99-3.12 (m, 1H), 4.09 (dd, 1H), 6.60 (br. s, 3H), 7.52-7.64 (m, 2H), 7.68 (br. d, 1H), 7.75 (br. s, 1H)。
Embodiment 135A
2-hydroxyl-1-[3-(trifluoromethyl) phenyl] and ethyl } methyl carbamic acid tertiary butyl ester
Figure 503552DEST_PATH_IMAGE139
Borine-tetrahydrofuran (THF) title complex (1M solution in THF, 438 mmol) of consumption 438 ml is introduced into, with ice-cooled.Then the N-Boc-2-of 35 g (110 mmol) (3-trifluoromethyl)-DL-glycine being divided several parts to add enters.Reaction mixture at room temperature stirs 2 hours, then mixes with several flake ices carefully.After gas is emitted end, on rotatory evaporator, remove desolventizing.Water-based residue mixes with saturated sodium bicarbonate solution, is then extracted with ethyl acetate three times.The organic phase dried over sodium sulfate merging is then removed desolventizing on rotatory evaporator.Residue is dissolved in acetonitrile and 2.5% concentration sodium bicarbonate aqueous solution.Then the heavy carbonic di-t-butyl ester that adds 25.18 ml (109.62 mmol), mixture at room temperature stirs 3 hours.On rotatory evaporator, remove acetonitrile.Residue is extracted with ethyl acetate three times, by dried over sodium sulfate, filters and remove desolventizing on rotatory evaporator.Residue mixes with borine-tetrahydrofuran (THF) title complex (1M solution in THF, 438 mmol) of 438 ml again, then at 70 DEG C, stirs 3 hours.It is aftertreatment again, by excessive by hydrogenchloride two
Figure 360649DEST_PATH_IMAGE064
4N solution in alkane adds in the mixture of complete aftertreatment, and it stirs a night.Afterwards, on rotatory evaporator, remove desolventizing.Residue is dry in HV, mixes again with borine-tetrahydrofuran (THF) title complex (1M solution in THF, 400 mmol) of 400 ml, then stirs a night.Its then aftertreatment and again, as mentioned above, reacts with the heavy carbonic di-t-butyl ester of 25.18 ml (109.62 mmol).The crude product obtaining after aftertreatment is purified with preparation property HPLC.The dry title compound that obtains 10.2 g (theoretical value 29%) in HV.
LC/MS [method 3]: R t=1.24 min; M/z=220 (M+H-BOC) +.
1h-NMR (400 MHz, DMSO-d 6): δ=7.53-7.68 (m, 4H), 5.20 (br.s, 0.5H (rotational isomer)), 5.04 (t, 1H), 5.03 (br. s, 0.5H (rotational isomer)), 3.77-3.98 (m, 2H), 2.60-2.83 (br.s, 3H), 1.37 (br. s, 9H).
Embodiment 136A
2-(amino-sulfonyl oxygen base)-1-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester
Figure 867985DEST_PATH_IMAGE140
The chloro sulfonyl isocyanate of consumption 171 μ L (1.97 mmol) at 0 DEG C, under violent stirring, mixes with the anhydrous formic acid of 74 μ L (1.97 mmol) in argon gas.After adding, reaction mixture solidifies within the several seconds.Add the methylene dichloride of consumption 2 ml.Then reaction mixture further stirs 1 hour at 0 DEG C, then at room temperature stirs 8 hours.After this it is cooled to 0 DEG C again, and the solution then forming in the methylene dichloride of 2 ml with the compound of embodiment 59A and the pyridine of 159 μ L (1.97 mmol) of 400 mg (1.31 mmol) mixes.Remove cooling bath, reaction mixture at room temperature stirs a night.For aftertreatment, add the water of 5 ml and the ethyl acetate of 5 ml.After 10 minutes, the ethyl acetate of 100 ml dilution for mixture, then washes with water twice and washs once with saturated sodium-chloride water solution.Organic phase dried over sodium sulfate is then removed desolventizing on rotatory evaporator.Preparation property HPLC[method 10 for residue] purify.Product fraction desolvation on rotatory evaporator.The dry title compound that obtains 260 mg (theoretical value 52%) in HV.
LC/MS [method 3]: R t=1.21 min; ESIneg.:m/z=383 (M-H) -.
H-NMR (400 MHz, DMSO-d 6): δ = 7.67 (s, 5H), 7.55 (s, 2H), 4.96 (d, 1H), 4.08-4.18 (m, 2H), 1.21-1.44 (m, 9H)。
Embodiment 137A
2-amino-2-[3-(trifluoromethyl) phenyl] and ethyl } carboxylamine ethyl ester hydrochloride
(non-racemic enantiomeric mixture)
Figure 519546DEST_PATH_IMAGE141
The solution that the compound of the embodiment 103A of 527 mg (1.40 mmol) forms in the methylene dichloride of 9.6 ml at room temperature with 9.4 ml (37 mmol) by hydrogenchloride two
Figure 564863DEST_PATH_IMAGE064
the 4M solution forming in alkane mixes, and then stirs 1 hour.Then, on rotatory evaporator, removing whole volatile components.Dry in HV of residue obtains the title compound of 437 mg (theoretical value 94%).
LC/MS [method 2]: R t=1.31 min; M/z=277 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.09 (t, 3H), 3.38-3.59 (m, 2H), 3.95 (q, 2H), 4.41-4.51 (m, 1H), 7.31 (br. t, 1H), 7.64-7.72 (m, 1H), 7.73-7.81 (m, 2H), 7.87 (br. s, 1H), 8.56 (br. s, 3H)。
According to the mode identical with embodiment 137A, prepare the following example.Output in each situation higher than 94% of theoretical value:
Figure 22389DEST_PATH_IMAGE142
Figure 463484DEST_PATH_IMAGE144
Figure 730517DEST_PATH_IMAGE145
Embodiment 158A
5-(4-chloro-phenyl-)-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-2,4-dihydro-3H-1,2,4-triazole-3-ketone
Figure 395034DEST_PATH_IMAGE147
The compound of the embodiment 3A of 1.08 g (3.3 mmol) is dissolved in the N,N-dimethylacetamide of 11 ml.Solution is reduced pressure and is removed atmosphericoxygen by use, saturated with argon gas.In argon gas to the ruthenium complexe RuCl (p-cymene) [(S, S)-Ts-DPEN)] (CAS No. 192139-90-5) that adds 21 mg (0.033 mmol) in this solution.Then the mixture that adds the formic acid of 0.63 ml (16.6 mmol) and the triethylamine of 0.27 ml (1.91 mmol), gained mixture at room temperature stirs 48 hours in the situation that there is no air.For aftertreatment, mixture is introduced in the 0.1N hydrochloric acid of 10 ml, then uses the ethyl acetate extracting twice of 20 ml.The organic phase merging is washed with saturated sodium bicarbonate aqueous solution, by dried over sodium sulfate, filters and under reduced pressure concentrates.Crude product is by silica gel chromatography purify (eluent: 1. cyclohexane/ethyl acetate 3:1,2. cyclohexane/ethyl acetate 1:1).This obtains the target compound of 830 mg (theoretical value 81%).
Enantiomer is excessive is that to utilize method 27c to record with red, orange, green, blue, yellow (ROGBY) be 96% ee.
(S)-enantiomer: R t=5.73 min
(R)-enantiomer: R t=6.82 min.
Embodiment 159A
[(tert-butoxycarbonyl) amino] (the chloro-2-fluorophenyl of 3-) acetic acid
Figure 653977DEST_PATH_IMAGE148
The fluoro-DL-phenylglycocoll of the chloro-2-of 3-of consumption 5 g (24.56 mmol) is suspended in to two
Figure 955776DEST_PATH_IMAGE064
in alkane, then add the 5% concentration sodium bicarbonate aqueous solution of 147 ml.Then add the heavy carbonic di-t-butyl ester of 5.36 g (24.56 mmol).Suspension at room temperature stirs a night.Ethyl acetate is added in white suspension, and these components stir together, and suction filtration goes out throw out.Mother liquor extracts.Water is extracted with ethyl acetate again.The organic phase dried over sodium sulfate merging, filters and concentrates on rotatory evaporator.The dry title compound that obtains 0.59 g (theoretical value 7.7%) in HV.
1M HCl acidifying for water, is then extracted with ethyl acetate twice.Extract dried over sodium sulfate, filters and concentrates on rotatory evaporator.The dry title compound that obtains 5.05 g (theoretical value 65.4%) in HV.
LC/MS [method 2]: R t=2.08 min; M/z=204 (M+H) +.
Embodiment 160A
[1-(the chloro-2-fluorophenyl of 3-)-2-hydroxyethyl] carboxylamine tertiary butyl ester
Figure 958367DEST_PATH_IMAGE149
In argon atmosphere by the compound dissolution of the embodiment 159A of 2 g (6.59 mmol) in the THF of 20 ml.Then solution be cooled to 0 DEG C and the triethylamine of dropping 0.918 ml (6.59 mmol) and the isobutyl chlorocarbonate of 0.94 ml (7.24 mmol).Reaction mixture stirs 1 hour subsequently at 0 DEG C.Afterwards, suspension is filled in chilled flask via plug thatch (Seitz) sintered glass material, with a small amount of THF washing.In second flask, add the solution being formed by the sodium borohydride of 747 mg (19.76 mmol) in the water of 3 ml, with ice-cooled.Violent stirring, drips filtrate at leisure.After 1 hour, this batch of material mixes with saturated sodium bicarbonate aqueous solution carefully.Then it extract by the ethyl acetate of 30 ml.Organic phase is again with saturated sodium bicarbonate aqueous solution washing, and washs once with saturated sodium-chloride water solution.Then it use dried over sodium sulfate, filters and remove on rotatory evaporator desolventizing.The dry title compound that obtains 1.74 g (theoretical value 75%) in HV, about 83% purity.
LC/MS [method 5]: R t=0.99 min; M/z=290 (M+H) +.
1H-NMR (400 MHz, CDCl 3): δ = 1.43 (s, 9H), 1.90-1.98 (m, 1H), 3.78-3.93 (m, 2H), 5.01-5.12 (m, 1H), 5.32-5.42 (m, 1H), 7.08 (t, 1H), 7.23 (t, 1H), 7.30-7.37 (m, 1H)。
Embodiment 161A
2-amino-2-(the chloro-2-fluorophenyl of 3-) ethylate hydrochlorate
Figure 544069DEST_PATH_IMAGE150
The compound of the embodiment 160A of 1.74 g (6.01 mmol) is joined in the methylene dichloride of 20 ml.Add 22 ml (88.00 mmol) by hydrogenchloride two
Figure 708334DEST_PATH_IMAGE064
the 4M solution forming in alkane.At room temperature stir after 1 hour, reaction mixture is evaporate to dryness on rotatory evaporator, and dry in HV.This obtains the title compound of 1.38 g (theoretical value 88%), about 87% purity.
LC/MS [method 5]: R t=0.27 min; M/z=190 (M+H) +.
Embodiment 162A
Carboxylamine 2-amino-2-(the chloro-2-fluorophenyl of 3-) ethyl ester hydrochloride
Figure 949960DEST_PATH_IMAGE151
The compound of the embodiment 160A of 243 mg (0.84 mmol) is incorporated in the acetonitrile of 10 ml in argon gas.Then at-15 DEG C, drip the chloro sulfonyl isocyanate of 102 μ L (1.17 mmol).After 30 minutes, reaction soln mixes with the water of 20 ml, at 60 DEG C, heats a night.Reaction mixture is cooled and is introduced in saturated sodium bicarbonate aqueous solution.Then it be extracted with ethyl acetate.Organic phase dried over sodium sulfate, filters and removes on rotatory evaporator desolventizing.Residue is dissolved in the methylene dichloride of 4 ml, then with 4 ml by hydrogenchloride two the 4M solution forming in alkane mixes.Form immediately throw out.After the follow-up churning time of 10 minutes, batch of material removes desolventizing on rotatory evaporator.The dry title compound that obtains 219 mg (theoretical value 77%) in HV, 79% purity.
LC/MS [method 5]: R t=0.27 min; M/z=233 (M+H) +.
Embodiment 163A
N-allyl group-2-(the bromo-4-chlorobenzene formacyl of 2-) hydrazine carboxylic acid amides
Figure 681604DEST_PATH_IMAGE152
By the bromo-4-chlorobenzene of the 2-hydrazides of consumption 10.0 g (40.1 mmol) at 50 DEG C of low suspensions in the THF of 100 ml, the solution then forming in the THF of 50 ml with the allyl group isocyanic ester of 3.59 ml (40.9 mmol) mixes.Proceed to stir 16 hours at 50 DEG C.Then this batch of material is cooled to room temperature, with the ether dilution of 50 ml.The solid of precipitation by suction filtration out, with the washing of a small amount of ether be dried in HV.This obtains the title compound of 11.30 g (theoretical value 85%).
LC/MS [method 6]: R t=1.81 min; M/z=332 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 3.69 (t, 2H), 5.04 (d, 1H), 5.16 (d, 1H), 5.76-5.88 (m, 1H), 6.45 (t, 1H), 7.58 (s, 2H), 7.84 (s, 1H), 8.10 (s, 1H), 10.07 (s, 1H)。
Embodiment 164A
4-allyl group-5-(the bromo-4-chloro-phenyl-of 2-)-2,4-dihydro-3H-1,2,4-triazole-3-ketone
Figure 344666DEST_PATH_IMAGE153
The compound dissolution of the embodiment 163A of 11.3 g (33.98 mmol), in the 3M aqueous sodium hydroxide solution of 61 ml (183.47 mmol), is then heated 36 hours under refluxing.Then this batch of material is cooled, and thin throw out is removed by filtration, and this filtrate, mixing with half concentrated hydrochloric acid of 28 ml (169.88 mmol) with under ice-cooled, reaches pH 10.This batch of material carries out suction filtration, dissolves product with methyl alcohol from throw out.On rotatory evaporator, remove methyl alcohol.Residue is dry in HV.This obtains the title compound of 9.78 g (theoretical value 69%), 75% purity.
LC/MS [method 2]: R t=1.88 min; M/z=314 and 316 (M+H) +.
1H-NMR (400 MHz, CDCl 3): δ = 4.19 (d, 2H), 4.93 (d, 1H), 5.09 (d, 1H), 5.64-5.74 (m, 1H), 7.32 (d, 1H), 7.39-7.44 (m, 1H), 7.72 (s, 1H), 9.45 (br. s., 1H)。
Embodiment 165A
[4-allyl group-3-(the bromo-4-chloro-phenyl-of 2-)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid methyl ester
Figure 808008DEST_PATH_IMAGE154
The compound of the embodiment 164A of 9.78 g (approximately 23.32 mmol, purity 75%) is dissolved in the acetonitrile of 75 ml.Then add the salt of wormwood of 3.55 g (25.65 mmol) and the methyl chloroacetate of 2.46 ml (27.98 mmol).Mixture stirs 5 hours under refluxing.After cooling, it carries out suction filtration.Filtrate is concentrated a little on rotatory evaporator, then washs with 30 ml ethyl acetate dilutions with 1M hydrochloric acid and each 30 ml of saturated sodium-chloride water solution.Organic phase dried over sodium sulfate, filters and removes on rotatory evaporator desolventizing.Residue is by silica gel chromatography purify (wash-out: cyclohexane/ethyl acetate 2:1).This obtains the title compound of 7.1 g (theoretical value 79%).
LC/MS [method 6]: R t=2.37 min; M/z=386 (M+H) +.
Embodiment 166A
[4-allyl group-3-(the bromo-4-chloro-phenyl-of 2-)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid
Figure 965451DEST_PATH_IMAGE155
The compound dissolution of the embodiment 156A of 4 g (10.35 mmol), in the methyl alcohol of 30 ml, is then mixed with the 1M lithium hydroxide solution of 15.5 ml (15.52 mmol).Mixture at room temperature stirs 2 hours.Then on rotatory evaporator, remove desolventizing.The water of 100 ml dilution for residue, washs by the ethyl acetate of 20 ml, then uses the in addition acidifying of 1M hydrochloric acid.It extracts by the ethyl acetate of 50 ml again.Organic phase thing dried over sodium sulfate, filters, concentrated and dry in HV on rotatory evaporator.This obtains the title compound of 3.61 g (theoretical value 94%).
LC/MS [method 3]: R t=0.99 min; M/z=372 and 374 (M+H) +.
1H-NMR (400 MHz, CDCl 3): δ = 4.21 (d, 2H), 4.72 (s, 2H), 4.94 (d, 1H), 5.09 (d, 1H), 5.63-5.76 (m, 1H), 7.31-7.43 (m, 2H), 7.71 (s, 1H)。
Embodiment 167A
The chloro-2-thienyl of 2-[(5-) carbonyl]-N-(2-methoxy ethyl) Hydrazinecarboxamidederivatives
5-chlorothiophene-2-carbohydrazide of consumption 3.1 g (17.55 mmol) is substantially suspended in subtly in the dry THF of 30 ml at 50 DEG C.Then solution 1-isocyano-2-methyl ethyl ether of 1.81 g (17.90 mmol) being formed in the THF of 30 ml drips into.Mixture stirs 2.5 hours at 50 DEG C.After being cooled to room temperature, on rotatory evaporator, except desolventizing, residue mixes with ether.Crystal by suction filtration out, with ether washing and dry in HV.This obtains the title compound of 4.87 g (theoretical value 100%).
1H-NMR (400 MHz, DMSO-d 6): δ = 3.14-3.21 (m, 2H), 3.28-3.36 (m, 5H), 6.52 (br. s., 1H), 7.22 (d, 1H), 7.70 (d, 1H), 7.97 (s, 1H), 10.24 (s, 1H)。
Embodiment 168A
5-(the chloro-2-thienyl of 5-)-4-(2-methoxy ethyl)-2,4-dihydro-3H-1,2,4-triazole-3-ketone
Figure 31814DEST_PATH_IMAGE157
The compound of the embodiment 167A of 4.85 g (17.46 mmol) is dissolved in the 3M aqueous sodium hydroxide solution of 17 ml (52.39 mmol), then under refluxing, heats 168 hours.In this process, 16,40, after 64 and 88 hours, add the solid sodium hydroxide of each part of 1.05 g (26.19 mmol, total 104.76 mmol).This batch of material uses 1M hcl acidifying to pH 10, the ethyl acetate extracting twice of 30 ml for mixture.The organic phase dried over sodium sulfate merging, filters, and on rotatory evaporator, is dried except desolventizing with in HV.This obtains the title compound of 2.44 g (theoretical value 54%).
1H-NMR (400 MHz, DMSO-d 6): δ = 3.20 (s, 3H), 3.53 (t, 2H), 3.92 (t, 2H), 7.24 (d, 1H), 7.51 (d, 1H), 12.04 (s, 1H)。
Embodiment 169A
[3-(the chloro-2-thienyl of 5-)-4-(2-methoxy ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid ethyl ester
Together with the salt of wormwood of the compound of the embodiment 168A of 2.4 g (9.24 mmol) and 2.55 g (18.48 mmol), be suspended in the acetonitrile of 48 ml.Then add the ethyl chloroacetate of 1.08 ml (10.17 mmol), mixture reflux 4.5 hours at 80 DEG C.Add the ethyl chloroacetate of other 113 mg (0.92 mmol), at 80 DEG C, stir 2 hours.Suspension filters via layer of silica gel, and it washs by ethyl acetate, and filtrate is concentrated on rotatory evaporator, and dry in HV.This obtains the title compound of 3.24 g (theoretical value 100%).
LC/MS [method 6]: R t=2.42 min; M/z=346 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.21 (t, 3H), 3.30 (s, 3H), 3.55 (t, 2H), 3.99 (t, 2H), 4.15 (q, 2H), 4.65 (s, 2H), 7.27 (d, 1H), 7.58 (d, 1H)。
Embodiment 170A
[3-(the chloro-2-thienyl of 5-)-4-(2-methoxy ethyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid
Figure 130537DEST_PATH_IMAGE159
The compound of the embodiment 169A of 3.2 g (9.25 mmol) is dissolved in the methyl alcohol of 28 ml.Then add the 20% concentration potassium hydroxide aqueous solution of 2.82 ml.Mixture at room temperature stirs 2 hours.Methyl alcohol fraction is concentrated reducing by half on rotatory evaporator.Mixture then dilute with water and the ethyl acetate with 15 ml extracts once.The concentrated hydrochloric acid acidifying in addition of 920 μ L for water, then uses the extracting twice of the ethyl acetate of 15 ml.The organic phase dried over sodium sulfate merging, filters and removes on rotatory evaporator desolventizing.The dry title compound that obtains 2.34 g (theoretical value 80%) in HV.
LC/MS [method 6]: R t=2.05 min; M/z=318 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 3.20 (s, 3H), 3.55 (t, 2H), 3.99 (t, 2H), 4.53 (s, 2H), 7.27 (d, 1H), 7.58 (d, 1H), 13.14 (br. s., 1H)。
Embodiment 171A
3-[(tert-butoxycarbonyl) amino]-3-(2-p-methoxy-phenyl) propionic acid methyl ester
Figure 293140DEST_PATH_IMAGE160
3-amino-3-of consumption 1.0 g (4.10 mmol) (2-p-methoxy-phenyl) propionic acid methyl ester is suspended in to two of 25 ml in the 5% concentration sodium bicarbonate aqueous solution of alkane and 27.5 ml.Then add the heavy carbonic di-t-butyl ester of 0.89 g (4.10 mmol).Mixture at room temperature stirs a night.The water blending of white suspension and 50 ml, then extracts three times by the ethyl acetate of 25 ml.The organic phase dried over mgso merging, filters and removes on rotatory evaporator desolventizing.This obtains the title compound of 1.34 g (theoretical value 100%).
LC/MS [method 4]: R t=1.06 min; M/z=310 (M+H) +.
Embodiment 172A
[3-hydroxyl-1-(2-p-methoxy-phenyl) propyl group] carboxylamine tertiary butyl ester
Figure 470361DEST_PATH_IMAGE161
The compound of the embodiment 171A of 1.34 g (4.33 mmol) is dissolved in the glycol dimethyl ether of 10 ml, then mixes with the sodium borohydride of 246 mg (6.50 mmol) and the lithium chloride of 37 mg (0.87 mmol).Mixture heats 16 hours at 85 DEG C.For aftertreatment, it is cooled to room temperature, carefully with the saturated Seignette salt aqueous solution of 10 ml.It extracts three times by the ethyl acetate of 20 ml.The organic phase dried over mgso merging, filters and removes on rotatory evaporator desolventizing.Crude product is by silica gel chromatography purify (wash-out: cyclohexane/ethyl acetate 9:1,7:3).This obtains the title compound of 348 mg (theoretical value 29%).
LC/MS [method 2]: R t=1.90 min; M/z=282 (M+H) +.
Embodiment 173A
3-amino-3-(2-p-methoxy-phenyl) propane-1-alcohol hydrochloride
Figure 156557DEST_PATH_IMAGE162
The compound of the embodiment 172A of 100 mg (0.36 mmol) is dissolved in the methylene dichloride of 2 ml, then add 1.63 ml (6.52 mmol) by hydrogenchloride two
Figure 176597DEST_PATH_IMAGE064
the 4M solution forming in alkane.Yellow solution at room temperature stirs 1 hour subsequently.Reaction mixture is evaporate to dryness on rotatory evaporator, then dry in HV.This obtains the title compound of 88 mg (theoretical value 100%).
1H-NMR (400 MHz, DMSO-d 6): δ = 1.90-2.11 (m, 2H), 3.28-3.44 (m, 2H), 3.83 (s, 3H), 4.52-4.61 (m, 1H), 4.76 (br. s., 1H), 7.02 (t, 1H), 7.09 (d, 1H), 7.40 (t, 2H), 8.21 (br. s., 3H)。
Embodiment 174A
Carboxylamine 3-amino-3-(2-p-methoxy-phenyl) propyl diester hydrochloride
Figure 290046DEST_PATH_IMAGE163
The compound of the embodiment 172A of 242 mg (0.86 mmol) is incorporated in the acetonitrile of 12 ml in argon atmosphere, and the chloro sulfonyl isocyanate that then drips 105 μ L (1.20 mmol) at-15 DEG C carries out blending.Reaction mixture stirs 30 minutes at-10 DEG C.Then add the water of 12 ml, mixture stirs a night at 60 DEG C.Reaction mixture is cooled, and is adjusted to alkalescence with saturated sodium bicarbonate aqueous solution, then with the ethyl acetate extraction of 10 ml three times.Organic phase is merged, by dried over mgso, filters and remove desolventizing on rotatory evaporator.Residue and 6 ml by hydrogenchloride two
Figure 215277DEST_PATH_IMAGE064
the 4M solution blending forming in alkane, each component stirs 10 minutes together, and mixture is concentrated on rotatory evaporator.Residue is dry in HV.This obtains the title compound of 186 mg (theoretical value 83%).
1H-NMR (400 MHz, DMSO-d 6): δ = 2.03-2.29 (m, 2H), 3.64-3.76 (m, 2H), 3.83 (s, 3H), 4.49-4.61 (m, 1H), 6.98-7.13 (m, 2H), 7.34-7.46 (m, 2H), 8.23 (br. s., 1H), 8.35 (br. s., 2H)。
Embodiment 175A
2-amino-2-(2,3-dichlorophenyl) ethanol
Figure 501902DEST_PATH_IMAGE164
Till being at room temperature stirred to together with amino-(2,3-dichlorophenyl) acetic acid of consumption 1.0 g (4.54 mmol) and borine-THF title complex (1M solution in THF) of 18.18 ml (18.18 mmol) and having reacted.For aftertreatment, add several flake ices.After gas is emitted end, mixture is adjusted to the pH value of 9-10 with 1M aqueous sodium hydroxide solution, then with t-butyl methyl ether extraction three times.The organic phase dried over sodium sulfate merging, filters and removes on rotatory evaporator desolventizing.The dry title compound that obtains 880 mg (theoretical value 91%) in HV.
LC/MS [method 5]: R t=0.39 min; M/z=206 and 208 (M+H) +.
Embodiment 176A
[3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid methyl ester
Figure 828978DEST_PATH_IMAGE165
The compound of the embodiment 76A of 1.2 g (3.32 mmol), platinum/carbon (5%) of 150 mg and methyl alcohol hydrogenation under standard hydrogen atmospheric pressure of 150 ml.For aftertreatment, leach catalyzer, filtrate is concentrated on rotatory evaporator.Preparation property HPLC purification (method 20) for crude product.Product fraction is merged, then on rotatory evaporator, removes desolventizing.The dry title compound that obtains 890 mg (theoretical value 73%) in HV.
LC/MS [method 4]: R t=1.00 min; M/z=364 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 2.55-2.68 (m, 2H), 3.69 (s, 3H), 4.01 (t, 2H), 4.70 (s, 2H), 7.61-7.72 (m, 4H)。
Embodiment 177A
[3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid
Figure 926378DEST_PATH_IMAGE166
The compound of the embodiment 176A of 1.27 g (3.49 mmol) is joined in the methyl alcohol of 200 ml and the water of 100 ml.Then add the 1M lithium hydroxide aqueous solution of 6.98 ml (6.98 mmol).Mixture at room temperature stirs 2 hours.In order to purify, add the 1N hydrochloric acid of 15 ml, mixture is methanol removal on rotatory evaporator.Residue dilutes and is extracted with ethyl acetate three times with the water of 100 ml.The organic phase dried over sodium sulfate merging, filters and removes on rotatory evaporator desolventizing, then dry in HV.This obtains the title compound of 1.11 g (theoretical value 91%).
LC/MS [method 2]: R t=1.92 min; M/z=350 (M+H) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 2.55-2.68 (m, 2H), 4.01 (t, 2H), 4.56 (s, 2H), 7.61-7.72 (m, 4H), 13.12 (br. s., 1H)。
Embodiment 178A
2-hydroxyl-1-[2-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester (enantiomer I)
Figure 73325DEST_PATH_IMAGE167
The compound of the embodiment 62A of 52.8 g is by the chirality property prepared HPLC[method 33] separate.Obtain first wash-out enantiomer (21g) according to chiral analysis HPLC (method 34) with 93% ee.
Chiral analysis HPLC [method 34]: R t=1.74 min.
For last wash-out enantiomer, referring to embodiment 179A.
Embodiment 179A
2-hydroxyl-1-[2-(trifluoromethyl) phenyl] and ethyl } carboxylamine tertiary butyl ester (enantiomer II)
From the separation of the compound of the embodiment 62A of 52.8 g, obtained last wash-out enantiomer (18.9 g, 99.7% ee) by method 33.
Chiral analysis HPLC [method 34]: R t=2.48 min.
LC/MS [method 3]: Rt=1.13 min; M/z=206 (M-BOC) +.
1H-NMR (400 MHz, DMSO-d 6): δ = 1.35 (s, 9H), 3.36-3.50 (m, 2H), 4.90-5.01 (m, 2H), 7.37-7.48 (m, 2H), 7.61-7.70 (m, 4H)。
The further separation that mixes under the same conditions fraction obtains the second enantiomer of other 4.0 g, has 99.5% ee.
Embodiment 180A
Carboxylamine 2-amino-2-[2-(trifluoromethyl) phenyl] ethyl ester hydrochloride (enantiomer II)
Figure 345224DEST_PATH_IMAGE168
The compound of the embodiment 179A of 250 mg (0.82 mmol) is incorporated in the acetonitrile of 9.76 ml in argon gas.At-15 DEG C, drip the chloro sulfonyl isocyanate of 100 μ L (1.15 mmol).After 30 minutes, reaction soln mixes with the water of 20 ml, at 60 DEG C, heats a night.Batch of material is cooled and is introduced in saturated sodium bicarbonate aqueous solution.It is extracted with ethyl acetate twice.The organic phase dried over sodium sulfate merging, filters and removes on rotatory evaporator desolventizing.The dry title compound that obtains 220 mg (theoretical value 100%) in HV.
LC/MS [method 4]: R t=0.39 min; M/z=249 (M+H) +.
Embodiment 181A
[(tert-butoxycarbonyl) amino] (2,3-dichlorophenyl) acetic acid
Figure 613525DEST_PATH_IMAGE169
The amino of consumption 500 mg (2.27 mmol) (2,3-dichlorophenyl) acetic acid is suspended in to two of 5 ml
Figure 513348DEST_PATH_IMAGE064
in alkane and 5% concentration sodium bicarbonate aqueous solution.Then add the heavy carbonic di-t-butyl ester of 522 μ L (2.27 mmol).This batch of material at room temperature stirs a night.Reaction mixture is extracted with ethyl acetate twice.1M HCl acidifying for water, is then extracted with ethyl acetate twice.The organic phase dried over sodium sulfate merging, filters and removes on rotatory evaporator desolventizing.The dry title compound that obtains 703 mg (theoretical value 94%) in HV.
LC/MS [method 5]: R t=1.02 min; M/z=318 and 320 (M-H) -.
Embodiment 182A
[1-(2,3-dichlorophenyl)-2-hydroxyethyl] carboxylamine tertiary butyl ester
The compound of the embodiment 181A of 702 mg (2.19 mmol) is dissolved in the THF of 7 ml in argon atmosphere, is then cooled to 0 DEG C.Then drip the triethylamine of 306 μ L (2.19 mmol) and the isobutyl chlorocarbonate of 313 μ L (2.41 mmol).Suspension stirs 1 hour at 0 DEG C.It is filled in chilled flask via plug thatch (Seitz) sintered glass material, with a small amount of THF washing.Gained filtrate is slowly added drop-wise in the solution that is cooled to 0 DEG C that the sodium borohydride of 249 mg (6.58 mmol) forms in the water of 1.5 ml.After 1 hour, this batch of material mixes with saturated sodium bicarbonate aqueous solution carefully, is then extracted with ethyl acetate.Organic phase is also again with saturated sodium bicarbonate aqueous solution washing, and washs once with saturated sodium-chloride water solution.It,, by dried over sodium sulfate, filters and removes on rotatory evaporator desolventizing.The dry title compound that obtains 537 mg (theoretical value 56%) in HV, 70% purity.
LC/MS [method 4]: R t=1.02 min; M/z=306 and 308 (M+H) +.
Embodiment 183A
Carboxylamine 2-amino-2-(2,3-dichlorophenyl) ethyl ester
Figure 177865DEST_PATH_IMAGE171
The compound of the embodiment 182A of 290 mg (approximately 0.95 mmol) is incorporated in the acetonitrile of 5 ml in argon gas.At-15 DEG C, drip the chloro sulfonyl isocyanate of 115 μ L (1.33 mmol).After 30 minutes, reaction soln mixes with the water of 20 ml, at 60 DEG C, heats a night.Reaction mixture is cooled and is introduced in saturated sodium bicarbonate aqueous solution.It is by the ethyl acetate extracting twice of 20 ml.The organic phase dried over sodium sulfate merging, filters and removes on rotatory evaporator desolventizing.The dry title compound that obtains 176 mg (theoretical value 66%) in HV, 89% purity.
LC/MS [method 2]: R t=1.07 min; M/z=249 (M+H) +.
Embodiment 184A
Carboxylamine 2-amino-2-[3-(trifluoromethyl) phenyl] ethyl ester
Figure 619997DEST_PATH_IMAGE172
The compound of the embodiment 59A of 93 mg (0.31 mmol) is incorporated in the acetonitrile of 4 ml in argon gas.At-15 DEG C, drip the chloro sulfonyl isocyanate of 37 μ L (0.43 mmol).After 30 minutes, reaction soln mixes with the water of 8 ml, at 60 DEG C, heats a night.Reaction mixture is cooled and is introduced in saturated sodium bicarbonate aqueous solution.It is by the ethyl acetate extracting twice of 10 ml.The organic phase dried over sodium sulfate merging, filters and removes on rotatory evaporator desolventizing.The dry title compound that obtains 66 mg (theoretical value 64%) in HV, 73% purity.
LC/MS [method 3]: R t=0.50 min; M/z=249 (M+H) +.
Embodiment 185A
[4-(4-chloro-phenyl-)-2-oxo-3-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2,3-dihydro-1H-imidazoles-1-yl] acetic acid (enantiomeric mixture)
[4-(4-chloro-phenyl-)-2-oxo-2 of consumption 1.0 g (3.75 mmol), 3-dihydro-1H-imidazoles-1-yl] acetic acid methyl ester is (according to WO 2007/134862, embodiment 323A preparation) with the 3-bromo-1 of 796 mg (4.13 mmol), 1,1-trifluoro propan-2-ol is dissolved in the acetone of 50 ml, at room temperature add the cesium carbonate of 1.47 g (4.50 mmol), mixture heats 16 hours under refluxing.For aftertreatment, it is cooled to room temperature, and mixes with the water of 50 ml.It is neutralized by adding 1M hydrochloric acid, then extracts three times by the ethyl acetate of 50 ml.The organic phase dried over sodium sulfate merging, filters and under reduced pressure concentrates.Preparation property HPLC purification [method 19] for crude product.This obtains the target compound of 171 mg (theoretical value 13%).
LC-MS [method 3] R t=1.02 min; MS [ESIpos]: m/z=365 (M+H) +.
Embodiment 186A
Ethyl carbamic acid 2-[(tert-butoxycarbonyl) amino]-2-[2-(trifluoromethyl) phenyl] ethyl ester (enantiomer-pure)
Figure 173655DEST_PATH_IMAGE174
The ethyl isocyanate of consumption 379 μ L (4.78 mmol) is joined in the solution being formed in the pyridine of 7 ml by the compound of embodiment 179A and the 4-dimethylaminopyridine of 15 mg (0.12 mmol) of 365 mg (1.20 mmol).Reaction mixture stirs a night at 50 DEG C.After being cooled to room temperature, mixture mixes with the ammonia solution (35% concentration in water) of 0.5 ml.On rotatory evaporator, remove volatile component.Residue is dissolved in a small amount of acetonitrile and 1N hydrochloric acid, by preparation property HPLC[method 20] separate.Containing fraction desolvation on rotatory evaporator of product, residue is dry in HV.This obtains the title compound of 380 mg (theoretical value 84%).
LC-MS [method 4] R t=1.09 min; MS [ESIpos]: m/z=377 (M+H) +.
Embodiment 187A
Ethyl carbamic acid 2-amino-2-[2-(trifluoromethyl) phenyl] ethyl ester hydrochloride (enantiomer-pure)
Figure 329830DEST_PATH_IMAGE175
The compound of the embodiment 186A of 345 mg (0.92 mmol) and 10 ml by hydrogenchloride two
Figure 939934DEST_PATH_IMAGE064
the 4N solution forming in alkane mixes, and mixture at room temperature stirs 30 minutes.Then on rotatory evaporator, remove whole volatile components.Residue (311 mg, theoretical value 100%) is title compound.
LC-MS [method 2] R t=1.20 min; MS [ESIpos]: m/z=277 (M+H) +
1H-NMR (500MHz, DMSO-d 6): δ [ppm]= 1.00 (t, 3H), 2.93-3.06 (m, 2H), 4.28 (dd, 1H), 4.38 (dd, 1H), 4.62-4.70 (m, 1H), 7.12 (br. t, 1H), 7.67 (t, 1H), 7.80-7.88 (m, 2H), 7.98 (d, 1H), 8.84 (br. s., 3H)。
Implement embodiment:
Embodiment 1
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-nitro-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 548770DEST_PATH_IMAGE176
By the compound of the embodiment 8A of 337 mg (0.92 mmol) and 274 mg (1.01 mmol, 1.1 equivalents) the compound of embodiment 13A, 247 mg (1.29 mmol, 1.4 equivalents) EDC and 174 mg (1.29 mmol, 1.4 equivalents) the DMF of HOBt and 8 ml together with introduce, then add the DIPEA of 192 μ L (1.10 mmol, 1.2 equivalents).Mixture at room temperature stirs 1 hour, then purifies with preparation property HPLC (method 10).This obtains the title compound of 445 mg (theoretical value 81%).
LC-MS [method 2]: R t=2.46 min; MS [ESIpos]: m/z=582 (M+H) +
1h NMR (DMSO-d 6, 400 MHz): δ=9.07 (d, 1H), 7.83 (s, 1H), 7.66-7.79 (m, 4H), 7.56-7.66 (m, 3H), 6.925 (d, 0.5H (1H, belong to diastereomer I)), 6.91 (d, 0.5H (1H, belong to diastereomer II)), 5.63-5.77 (m, 1H), 5.08 (dd, 1H), 4.95 (dd, 1H), 4.53 (s, 1H (2H, belong to diastereomer I)), 4.43-4.61 (m [AB], 1H (2H, belong to diastereomer II)), 4.18-4.37 (m, 1H), 3.96 (br. d, 1H), 3.83 (dd, J=14.7, 9.5 Hz, 1H).
Separate the diastereomer of embodiment 1 by the preparation chromatography (method 11a) going up mutually in chirality: referring to embodiment 2 and embodiment 3.
Embodiment 2
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-nitro-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 519000DEST_PATH_IMAGE176
The first wash-out diastereomer being obtained from the separation of embodiment 1 by method 11a.
LC-MS [method 2]: R t=2.43 min; MS [ESIpos]: m/z=582 (M+H) +
Analyze chirality HPLC [method 12a]: R t=4.40 min.
Embodiment 3
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-nitro-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 529681DEST_PATH_IMAGE176
The last wash-out diastereomer being obtained from the separation of embodiment 1 by method 11a.
LC-MS [method 2]: R t=2.44 min; MS [ESIpos]: m/z=582 (M+H) +
Analyze chirality HPLC [method 12a]: R t=5.37 min.
Embodiment 4
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-nitro-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 310687DEST_PATH_IMAGE177
According to the mode identical with embodiment 1, obtain the title compound of 880 mg (theoretical value 72%) from the compound of embodiment 8A of 766 mg (2.09 mmol) and the compound of the embodiment 17A of 656 mg (2.30 mmol).
LC-MS [method 5]: R t=1.12 min; MS [ESIpos]: m/z=582 (M+H) +
Separate the diastereomer of embodiment 4 by the preparation chromatography (method 11b) going up mutually in chirality: referring to embodiment 5 and embodiment 6.
Embodiment 5
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-nitro-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
The first wash-out diastereomer (419 mg) being obtained from the diastereomeric separation of the compound of the embodiment 4 of 880 mg by method 11b.
LC-MS [method 2]: R t=2.40 min; MS [ESIpos]: m/z=582 (M+H) +
Analyze chirality HPLC [method 12a]: R t=4.20 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 9.20 (d, 1H), 7.82 (d, 1H), 7.80-7.71 (m, 4H), 7.63 (d, 2H), 7.58 (t, 1H), 6.92 (d, 1H), 6.02-5.94 (m, 1H), 4.92 (dd, 1H), 4.82 (dd, 1H), 4.49 (s, 2H), 4.32-4.19 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H)。
Embodiment 6
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-nitro-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 993789DEST_PATH_IMAGE177
The last wash-out diastereomer (417 mg) being obtained from the diastereomeric separation of the compound of the embodiment 4 of 880 mg by method 11b.
LC-MS [method 2]: R t=2.39 min; MS [ESIpos]: m/z=582 (M+H) +
Analyze chirality HPLC [method 12a]: R t=5.64 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 9.20 (d, 1H), 7.82 (d, 1H), 7.80-7.70 (m, 4H), 7.62 (d, 2H), 7.58 (t, 1H), 6.90 (d , 1H), 6.00-5.93 (m, 1H), 4.92 (dd, 1H), 4.82 (dd, 1H), 4.48 (dd [AB], 2H), 4.31-4.20 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H)。
Embodiment 7
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{1-[2,3-dichlorophenyl]-2-nitro-ethyl } ethanamide (non-enantiomer mixture)
Figure 124556DEST_PATH_IMAGE178
According to the mode identical with embodiment 1, obtain the title compound of 638 mg (theoretical value 91%) from the compound of embodiment 8A of 422 mg (1.16 mmol) and the compound of the embodiment 21A of 363 mg (1.27 mmol).
LC-MS [method 5]: R t=1.13 min; MS [ESIpos]: m/z=582 (M+H) +
Separate the diastereomer of embodiment 7 by the preparation chromatography (method 11c) going up mutually in chirality: referring to embodiment 8 and embodiment 9.
Embodiment 8
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{1-[2,3-dichlorophenyl]-2-nitro-ethyl } ethanamide (diastereomer I)
Figure 325730DEST_PATH_IMAGE178
The first wash-out diastereomer (181 mg) being obtained from the diastereomeric separation of the compound of the embodiment 7 of 630 mg by method 11c.
LC-MS [method 2]: R t=2.44 min; MS [ESIpos]: m/z=582 (M+H) +
Analyze chirality HPLC [method 12b]: R t=5.81 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 9.22 (d, 1H), 7.74 (d, 2H), 7.67-7.61 (m, 3H), 7.55 (dd, 1H), 7.43 (t, 1H), 6.91 (d, 1H), 6.04-5.97 (m, 1H), 5.01 (dd, 1H), 4.81 (dd, 1H), 4.58-4.47 (m[AB], 2H), 4.33-4.21 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H)。
Embodiment 9
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{1-[2,3-dichlorophenyl]-2-nitro-ethyl } ethanamide (diastereomer II)
Figure 643579DEST_PATH_IMAGE178
The last wash-out diastereomer (281 mg) being obtained from the diastereomeric separation of the compound of the embodiment 7 of 630 mg by method 11c.
LC-MS [method 2]: R t=2.44 min; MS [ESIpos]: m/z=582 (M+H) +
Analyze chirality HPLC [method 12b]: R t=6.66 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 9.22 (d, 1H), 7.74 (d, 2H), 7.66 (d, 1H), 7.63 (d, 2H), 7.55 (dd, 1H), 7.44 (t, 1H), 6.90 (d, 1H), 6.04-5.96 (m, 1H), 5.01 (dd, 1H), 4.81 (dd, 1H), 4.58-4.47 (m[AB], 2H), 4.31-4.20 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H)。
Embodiment 10
N-{2-amino-1-[3-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetamide hydrochloride (non-enantiomer mixture)
The indium powder of the compound of the embodiment 1 of 45 mg (77 μ mol) and 40 mg (348 μ mol) and the concentrated hydrochloric acid of 42 μ L are blended in the THF of 0.5 ml, and mixture at room temperature stirs 2 hours.Then preparation property HPLC purification (method 10) for mixture.Containing the fraction of product and the 1N hydrochloric acid blending of 2 ml, then concentrated on rotatory evaporator.In HV, the dry title compound that obtains 21 mg (theoretical value 46%), is non-enantiomer mixture.
LC-MS [method 5]: R t=0.85 min; MS [ESIpos]: m/z=552 (M+H) +.
Embodiment 11
N-{2-amino-1-[3-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetamide hydrochloride (diastereomer I)
At continuous flow hydrogenation apparatus (H-Cube, from Thales Nano, Budapest obtains, HC-2-SS type) in, the solution that the compound of the embodiment 2 of 325 mg (0.56 mmol) forms in the methyl alcohol of 50 ml carries out hydrogenation (condition: Raney nickel box, the flow rate of 1 ml/min, 45 DEG C, standard hydrogen atmospheric pressure).On rotatory evaporator, remove methyl alcohol, preparation property HPLC purification (method 10) for residue.Containing the fraction of product and the 1N hydrochloric acid blending of 20 ml, then concentrated on rotatory evaporator.The dry title compound that obtains 266 mg (theoretical value 81%) in HV.
LC-MS [method 4]: R t=0.90 min; MS [ESIpos]: m/z=552 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.99 (d, 1H), 7.99-8.21 (m, 3H), 7.67-7.80 (m, 5H), 7.57-7.67 (m, 3H), 6.89 (d, 1H), 5.18-5.28 (m, 1H), 4.50-4.67 (m [AB], 2H), 4.21-4.34 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.13-3.28 (m, 2H)。
Embodiment 12
N-{2-amino-1-[3-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetamide hydrochloride (diastereomer II)
According to the mode identical with embodiment 11, but at room temperature, the compound of the embodiment 3 of 316 mg (0.54 mmol) is hydrogenated.This obtains the title compound of 180 mg (theoretical value 56%).
LC-MS [method 4]: R t=0.89 min; MS [ESIpos]: m/z=552 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 9.00 (d, 1H), 8.12 (br.s, 3H), 7.66-7.81 (m, 5H), 7.57-7.66 (m, 3H), 6.94 (d, 1H), 5.20-5.29 (m, 1H), 4.50-4.66 (m [AB], 2H), 4.20-4.33 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.13-3.28 (m, 2H)。
Embodiment 13
N-{2-amino-1-[2-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetamide hydrochloride (diastereomer I)
Figure 131488DEST_PATH_IMAGE180
According to the mode identical with embodiment 11, but at room temperature, the compound of the embodiment 5 of 415 mg (0.71 mmol) is hydrogenated in 100 ml methyl alcohol.This obtains the title compound of 330 mg (theoretical value 79%).
LC-MS [method 6]: R t=1.57 min; MS [ESIpos]: m/z=552 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 9.11-9.18 (m, 1H), 8.24 (br.s, 3H), 7.87 (d, 1H), 7.71-7.78 (m, 4H), 7.60-7.65 (m, 2H), 7.55 (t, 1H), 6.93 (d, 1H), 5.44-5.53 (m, 1H), 4.66 (dd, 1H), 4.52 (d, 1H), 4.19-4.30 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.07-3.22 (m, 1H), 2.95-3.07 (m, 1H)。
Embodiment 14
N-{2-amino-1-[2-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetamide hydrochloride (diastereomer II)
Figure 997944DEST_PATH_IMAGE180
According to the mode identical with embodiment 11, but at room temperature, the compound of the embodiment 6 of 415mg (0.71 mmol) is hydrogenated in 100 ml methyl alcohol.This obtains the title compound of 330 mg (theoretical value 79%).
LC-MS [method 6]: R t=1.56 min; MS [ESIpos]: m/z=552 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 9.08-9.17 (m, 1H), 8.21 (br.s, 3H), 7.86 (d, 1H), 7.70-7.78 (m, 4H), 7.62 (d, 2H), 7.53-7.59 (m, 1H), 6.88 (d, 1H), 5.44-5.52 (m, 1H), 4.67 (d, 1H), 4.51 (d, 1H), 4.20-4.32 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.09-3.22 (m, 1H), 2.96-3.08 (m, 1H)。
Embodiment 15
N-[2-amino-1-(2,3-dichlorophenyl) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetamide hydrochloride (diastereomer I)
Figure 837724DEST_PATH_IMAGE181
According to the mode identical with embodiment 11, but at room temperature, the compound of the embodiment 8 of 180mg (0.31 mmol) is hydrogenated in 50 ml methyl alcohol.This obtains the title compound of 116 mg (theoretical value 64%).
LC-MS [method 6]: R t=1.61 min; MS [ESIpos]: m/z=552 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 9.15 (d, 1H), 8.23 (br.s, 3H), 7.75 (d, 2H), 7.57-7.66 (m, 4H), 7.42 (t, 1H), 6.93 (d, 1H), 5.53 (td, 1H), 4.52-4.68 (m, 2H), 4.19-4.31 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.06-3.18 (m, 2H)。
Embodiment 16
N-[2-amino-1-(2,3-dichlorophenyl) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } acetamide hydrochloride (diastereomer II)
Figure 380700DEST_PATH_IMAGE181
According to the mode identical with embodiment 11, but at room temperature, the compound of the embodiment 9 of 280mg (0.48 mmol) is hydrogenated in 80 ml methyl alcohol.This obtains the title compound of 177 mg (theoretical value 63%).
LC-MS [method 5]: R t=0.84 min; MS [ESIpos]: m/z=552 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 9.23 (d, 1H), 8.26 (br.s, 3H), 7.74 (d, 2H), 7.58-7.67 (m, 4H), 7.42 (t, 1H), 6.90 (d, 1H), 5.52 (q, 1H), 4.52-4.69 (m [AB], 2H), 4.22-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.08-3.18 (m, 2H)。
Embodiment 17
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(formamido-)-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 938721DEST_PATH_IMAGE182
By using in the method described in embodiment 1, obtain title compound from the compound of embodiment 8A of 62 mg (0.17 mmol) and the compound of the embodiment 24A of 50 mg (0.19 mmol): 80 mg (theoretical value 82%).
LC-MS [method 5]: R t=1.06 min; MS [ESIpos]: m/z=580 (M+H) +
Separate the diastereomer of embodiment 17 by the preparation chromatography (method 17a) going up mutually in chirality: referring to embodiment 18 and embodiment 19.
Embodiment 18
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(formamido-)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 530239DEST_PATH_IMAGE182
The first wash-out diastereomer (28 mg) being obtained from the separation of the compound of the embodiment 17 of 80 mg by method 17a.
LC-MS [method 4]: R t=1.04 min; MS [ESIpos]: m/z=580 (M+H) +
Analyze chirality HPLC [method 18a]: R t=5.28 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.72 (d, 1H), 8.17 (t, 1H), 7.99 (s, 1H), 7.75 (d, 2H), 7.69 (s, 1H), 7.55-7.68 (m, 5H), 6.92 (d, 1H), 5.00-5.08 (m, 1H), 4.51 (s, 2H), 4.21-4.35 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.46-3.55 (m, 1H), 3.32-3.40 (m, 1H)。
Embodiment 19
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(formamido-)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 303154DEST_PATH_IMAGE182
The last wash-out diastereomer (30 mg) being obtained from the separation of the compound of the embodiment 17 of 80 mg by method 17a.
LC-MS [method 4]: R t=1.04 min; MS [ESIpos]: m/z=580 (M+H) +
Analyze chirality HPLC [method 18a]: R t=15.29 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.73 (d, 1H), 8.16 (t, 1H), 7.99 (s, 1H), 7.74 (d, 2H), 7.69 (s, 1H), 7.56-7.67 (m, 5H), 6.89 (d, 1H), 5.00-5.08 (m, 1H), 4.45-4.56 (m [AB], 2H), 4.22-4.34 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.47-3.55 (m, 1H), 3.32-3.40 (m, 1H)。
Embodiment 20
N-{2-(kharophen)-1-[3-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (non-enantiomer mixture)
Figure 954715DEST_PATH_IMAGE183
By using in the method described in embodiment 1, obtain title compound from the compound of embodiment 8A of 82 mg (0.22 mmol) and the compound of the embodiment 26A of 70 mg (0.25 mmol): 110 mg (theoretical value 75%).
LC-MS [method 2] R t=2.26/2.28 min; MS [ESIpos]: m/z=594 (M+H) +
Separate two kinds of diastereomers by the preparation chromatography (method 17e) going up mutually in chirality: referring to embodiment 21 and 22.
Embodiment 21
N-{2-(kharophen)-1-[3-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer I)
Figure 796769DEST_PATH_IMAGE183
The first wash-out diastereomer (42 mg) being obtained from the separation of the compound of the embodiment 20 of 110 mg by method 17e.
LC-MS [method 4]: R t=1.06 min; MS [ESIpos]: m/z=594 (M+H) +
Analyze chirality HPLC [method 18a]: R t=4.18 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.67 (d, 1H), 8.01 (t, 1H), 7.76 (d, 2H), 7.54-7.68 (m, 6H), 6.94 (d, 1H), 4.96-5.04 (m, 1H), 4.45-4.56 (m [AB], 2H), 4.25-4.36 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.36-3.46 (m, 1H), 3.27-3.35 (m, 1H), 1.75 (s, 3H)。
Embodiment 22
N-{2-(kharophen)-1-[3-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer II)
Figure 191979DEST_PATH_IMAGE183
The last wash-out diastereomer (43 mg) being obtained from the separation of the compound of the embodiment 20 of 110 mg by method 17e.
LC-MS [method 4]: R t=1.08 min; MS [ESIpos]: m/z=594 (M+H) +
Analyze chirality HPLC [method 18a]: R t=9.35 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.68 (d, 1H), 8.01 (t, 1H), 7.75 (d, 2H), 7.55-7.68 (m, 6H), 6.92 (d, 1H), 4.96-5.03 (m, 1H), 4.45-4.55 (m, 2H), 4.24-4.36 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.37-3.45 (m, 1H), 3.26-3.36 (m, 1H), 1.75 (s, 3H)。
Embodiment 23
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(methyl sulphonyl) amino]-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 819400DEST_PATH_IMAGE184
The mixing that the compound (0.14 mmol) of the embodiment 8A of 52 mg and the HOBt of 27 mg (0.20 mmol) form in the DMF of 2 ml is introduced into, mix with the EDC of 38 mg (0.20 mmol), then at room temperature stir 20 minutes.Then the compound of embodiment 50A and the DIPEA of 35 μ L (0.20 mmol) that add 50 mg (0.16 mmol), reaction mixture further at room temperature stirs a night.Whole mixture is purified completely by preparation property HPLC (method 10).This obtains the title compound of 68 mg (theoretical value 76%).
LC-MS [method 2]: R t=2.32 min; MS [ESIpos]: m/z=630 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.70 (d, 1H), 7.71-7.78 (m, 3H), 7.57-7.70 (m, 5H), 7.24 (t, 1H), 6.92 (d, 1H), 5.02-5.11 (m, 1H), 4.48-4.60 (m [AB], 2H), 4.23-4.34 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.25-3.33 (m, 2H), 2.86 (s, 3H)。
Embodiment 24
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(methyl sulphonyl) amino]-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Compound (0.12 mmol) and 23 mg (0.17 mmol of the embodiment 8A of 45 mg, 1.4 equivalents) the mixing that forms in the DMF of 1.7 ml of HOBt be introduced into, with 33 mg (0.17 mmol, 1.4 equivalents) EDC mix, then at room temperature stir 20 minutes.Then the compound of embodiment 47A and the DIPEA of 30 μ L (0.17mmol, 1.4 equivalents) that add 43 mg (0.14 mmol, 1.1 equivalents), reaction mixture further at room temperature stirs a night.Preparation property HPLC purification (method 10) for whole mixture.This obtains the title compound of 51 mg (theoretical value 66%).
LC-MS [method 2]: R t=2.30 min; MS [ESIpos]: m/z=630 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.72 (d, 1H), 7.72-7.77 (m, 3H), 7.57-7.70 (m, 5H), 7.24 (t, 1H), 6.89 (d, 1H), 5.02-5.10 (m, 1H), 4.46-4.62 (m [AB], 2H), 4.22-4.32 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.25-3.31 (m, 2H), 2.86 (s, 3H)。
Embodiment 25
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(methyl sulphonyl) amino]-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 971213DEST_PATH_IMAGE185
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 54 mg (0.15 mmol) and the compound of the embodiment 53A of 52 mg (0.16 mmol): 73 mg (theoretical value 78%).
LC-MS [method 5]: R t=1.07 min; MS [ESIpos]: m/z=630 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.75 (d, 1H), 7.68-7.80 (m, 5H), 7.62 (d, 2H), 7.51 (t, 1H), 7.41 (t, 1H), 6.93 (d, 1H), 5.30-5.38 (m, 1H), 4.61 (d, 1H), 4.47 (d, 1H), 4.22-4.33 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.12-3.27 (m, 2H), 2.88 (s, 3H)。
Embodiment 26
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(methyl sulphonyl) amino]-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 170113DEST_PATH_IMAGE185
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 57 mg (0.16 mmol) and the compound of the embodiment 54A of 55 mg (0.17 mmol): 70 mg (theoretical value 71%).
LC-MS [method 5]: R t=1.06 min; MS [ESIpos]: m/z=630 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.76 (d, 1H), 7.70-7.80 (m, 5H), 7.61 (d, 2H), 7.52 (t, 1H), 7.41 (t, 1H), 6.89 (d, 1H), 5.29-5.37 (m, 1H), 4.62 (d, 1H), 4.46 (d, 1H), 4.21-4.34 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.13-3.27 (m, 2H), 2.88 (s, 3H)。
Embodiment 27
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl }-N-{1-(2,3-dichlorophenyl)-2-[(methyl sulphonyl) amino] ethyl } ethanamide (diastereomer I)
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 50 mg (0.14 mmol) and the compound of the embodiment 57A of 48 mg (0.15 mmol): 64 mg (theoretical value 74%).
LC-MS [method 5]: R t=1.08 min; MS [ESIpos]: m/z=630 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.76 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.59 (dd, 1H), 7.51 (dd, 1H), 7.40 (t, 1H), 7.36 (t, 1H), 6.92 (d, 1H), 5.37 (td, 1H), 4.49-4.62 (m [AB], 2H), 4.22-4.34 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.25-3.33 (m, 1H), 3.17 (ddd, 1H), 2.90 (s, 3H)。
Embodiment 28
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl }-N-{1-(2,3-dichlorophenyl)-2-[(methyl sulphonyl) amino] ethyl } ethanamide (diastereomer II)
Figure 660053DEST_PATH_IMAGE186
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 51 mg (0.14 mmol) and the compound of the embodiment 58A of 49 mg (0.15 mmol): 59 mg (theoretical value 67%).
LC-MS [method 5]: R t=1.08 min; MS [ESIpos]: m/z=630 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.77 (d, 1H), 7.74 (d, 2H), 7.58-7.64 (m, 3H), 7.51 (br.d, 1H), 7.42 (t, 1H), 7.36 (t, 1H), 6.89 (d, 1H), 5.37 (td, 1H), 4.46-4.64 (m [AB], 2H), 4.21-4.31 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.25-3.35 (m, 1H), 3.17 (ddd, 1H), 2.89 (s, 3H)。
Embodiment 29
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(ethylsulfonyl) amino]-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 414383DEST_PATH_IMAGE187
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 40 mg (0.11 mmol) and the compound of the embodiment 48A of 40 mg (0.12 mmol): 57 mg (theoretical value 81%).
LC-MS [method 5]: R t=1.11 min; MS [ESIpos]: m/z=644 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.68 (d, 1H), 7.71-7.78 (m, 3H), 7.57-7.69 (m, 5H), 7.27 (t, 1H), 6.93 (d, 1H), 5.00-5.08 (m, 1H), 4.48-4.58 (m [AB], 2H), 4.23-4.34 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.27 (t, 2H), 2.94 (dd, 2H), 1.11 (t, 3H)。
Embodiment 30
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(ethylsulfonyl) amino]-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 479291DEST_PATH_IMAGE188
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 40 mg (0.11 mmol) and the compound of the embodiment 49A of 40 mg (0.12 mmol): 56 mg (theoretical value 80%).
LC-MS [method 2]: R t=2.35 min; MS [ESIpos]: m/z=644 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.69 (d, 1H), 7.71-7.76 (m, 3H), 7.57-7.69 (m, 5H), 7.26 (t, 1H), 6.89 (d, 1H), 5.00-5.07 (m, 1H), 4.46-4.61 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.27 (t, 2H), 2.90-2.98 (m, 2H), 1.10 (t, 3H)。
Embodiment 31
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(ethylsulfonyl) amino]-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 2676DEST_PATH_IMAGE189
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 40 mg (0.11 mmol) and the compound of the embodiment 51A of 40 mg (0.12 mmol): 53 mg (theoretical value 75%).
LC-MS [method 5]: R t=1.10 min; MS [ESIpos]: m/z=644 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.74 (d, 1H), 7.68-7.79 (m, 5H), 7.62 (d, 2H), 7.51 (t, 1H), 7.46 (t, 1H), 6.93 (d, 1H), 5.27-5.35 (m, 1H), 4.43-4.63 (m [AB], 2H), 4.22-4.34 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.10-3.26 (m, 2H), 2.91-3.02 (m, 2H), 1.16 (t, 3H)。
Embodiment 32
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(ethylsulfonyl) amino]-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 979990DEST_PATH_IMAGE189
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 40 mg (0.11 mmol) and the compound of the embodiment 52A of 40 mg (0.12 mmol): 51 mg (theoretical value 72%).
LC-MS [method 2]: R t=2.31 min; MS [ESIpos]: m/z=644 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.74 (d, 1H), 7.69-7.79 (m, 5H), 7.61 (d, 2H), 7.51 (t, 1H), 7.45 (t, 1H), 6.89 (d, 1H), 5.26-5.36 (m, 1H), 4.42-4.65 (m [AB], 2H), 4.20-4.32 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.10-3.25 (m, 2H), 2.90-3.02 (m, 2H), 1.15 (t, 3H)。
Embodiment 33
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl }-N-{1-(2,3-dichlorophenyl)-2-[(ethylsulfonyl) amino] ethyl } ethanamide (diastereomer I)
Figure 221616DEST_PATH_IMAGE190
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 40 mg (0.11 mmol) and the compound of the embodiment 55A of 40 mg (0.12 mmol): 54 mg (theoretical value 77%).
LC-MS [method 2]: R t=2.35 min; MS [ESIpos]: m/z=644 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.72 (d, 1H), 7.75 (d, 2H), 7.63 (d, 2H), 7.59 (dd, 1H), 7.50 (d, 1H), 7.36-7.43 (m, 2H), 6.92 (d, 1H), 5.31-5.39 (m, 1H), 4.49-4.61 (m [AB], 2H), 4.23-4.33 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.23-3.29 (m, 1H), 3.11-3.20 (m, 1H), 2.92-3.03 (m, 2H), 1.15 (t, 3H)。
Embodiment 34
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl }-N-{1-(2,3-dichlorophenyl)-2-[(ethylsulfonyl) amino] ethyl } ethanamide (diastereomer II)
Figure 824636DEST_PATH_IMAGE191
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 40 mg (0.11 mmol) and the compound of the embodiment 56A of 40 mg (0.12 mmol): 56 mg (theoretical value 80%).
LC-MS [method 2]: R t=2.34 min; MS [ESIpos]: m/z=644 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.74 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.60 (dd, 1H), 7.50 (d, 1H), 7.37-7.43 (m, 2H), 6.89 (d, 1H), 5.34 (td, 1H), 4.46-4.63 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.23-3.30 (m, 1H), 3.11-3.21 (m, 1H), 2.92-3.03 (m, 2H), 1.15 (t, 3H)。
Embodiment 35
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-hydroxyl-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 202527DEST_PATH_IMAGE192
The compound (300 mg, 0.98 mmol) of embodiment 59A by with hydrogenchloride two
Figure 616322DEST_PATH_IMAGE064
4N solution in alkane stirs together 10 minutes and goes protection, removes subsequently volatile constituent and be dried in HV on rotatory evaporator.The residue obtaining is dissolved in the DMF of 3 ml, then mixes with the DIPEA of 202 μ L (1.16 mmol).In independent flask, the compound of the embodiment 8A of 327 mg (0.89 mmol) and the EDC of 257 mg (1.34 mmol) and the HOBt of 181 mg (1.34 mmol) at room temperature stir 20 minutes together with in the DMF of 4.8 ml.This solution is added in the solution of amino alcohol, then mixture at room temperature reacts 20 minutes.Then add the 1N hydrochloric acid of 1 ml, preparation property HPLC purification (method 10) for complete reaction mixture.This obtains the title compound of 324 mg (theoretical value 66%).
LC-MS [method 5]: R t=1.07 min; MS [ESIpos]: m/z=553 (M+H) +
Separate two kinds of diastereomers by the preparation chromatography (method 17b) going up mutually in chirality: referring to embodiment 36 and 37.
Embodiment 36
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-hydroxyl-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
The first wash-out diastereomer (147 mg) being obtained from the separation of the compound of the embodiment 35 of 315 mg by method 17b.
Analyze chirality HPLC [method 18a]: R t=9.82 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 8.71 (d, 1H), 7.75 (d, 2H), 7.69 (s, 1H), 7.53-7.66 (m, 5H), 6.91 (d, 1H), 5.02 (t, 1H), 4.91-4.98 (m, 1H), 4.49-4.59 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.62 (t, 2H)。
Embodiment 37
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-hydroxyl-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 486375DEST_PATH_IMAGE192
The last wash-out diastereomer (147 mg) being obtained from the separation of the compound of the embodiment 35 of 315 mg by method 17b.
Analyze chirality HPLC [method 18a]: R t=13.98 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.72 (d, 1H), 7.74 (d, 2H), 7.69 (s, 1H), 7.52-7.66 (m, 5H), 6.89 (d, 1H), 5.02 (t, 1H), 4.91-4.98 (m, 1H), 4.49-4.60 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.62 (t, 2H)。
Embodiment 38
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-hydroxyl-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 718773DEST_PATH_IMAGE193
The compound of the embodiment 61A of the compound of the embodiment 8A of 278 mg (0.76 mmol) and 184 mg (0.76 mmol), the EDC of 219 mg (1.14 mmol) is introduced in the DMF of 18 ml together with the HOBt of 154 mg (1.14 mmol), then mix with the DIPEA of 265 μ L (1.52 mmol).Mixture at room temperature stirs a night, with the 1N mixed in hydrochloric acid of 1 ml, then by preparation property HPLC purification (method 10).This obtains the title compound of 310 mg (theoretical value 74%).
LC-MS [method 4]: R t=1.03 min; MS [ESIpos]: m/z=553 (M+H) +
Separate two kinds of diastereomers by the preparation chromatography (method 17e) going up mutually in chirality: referring to embodiment 39 and 40.
Embodiment 39
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-hydroxyl-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 490420DEST_PATH_IMAGE194
The first wash-out diastereomer (134 mg) being obtained from the separation of the compound of the embodiment 38 of 310 mg by method 17e.This product is purified by the property prepared HPLC (method 10), removes solvent residues.This obtains the title compound of 99 mg.
Analyze chirality HPLC [method 18a]: R t=2.12 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.79 (d, 1H), 7.73 (d, 2H), 7.64-7.71 (m, 3H), 7.61 (d, 2H), 7.44-7.51 (m, 1H), 6.89 (d, 1H), 5.17-5.24 (m, 1H), 5.14 (t, 1H), 4.52 (q [AB], 2H), 4.19-4.31 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.54-3.62 (m, 1H), 3.44-3.53 (m, 1H)。
Embodiment 40
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-hydroxyl-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 254108DEST_PATH_IMAGE195
The last wash-out diastereomer (156 mg) being obtained from the separation of the compound of the embodiment 38 of 310 mg by method 17e.This product is also purified by preparation property HPLC (method 10), removes solvent residues.This obtains the title compound of 128 mg.
Analyze chirality HPLC [method 18a]: R t=5.59 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.79 (d, 1H), 7.74 (d, 2H), 7.65-7.70 (m, 3H), 7.62 (d, 2H), 7.44-7.50 (m, 1H), 6.91 (d, 1H), 5.18-5.26 (m, 1H), 5.15 (t, 1H), 4.46-4.57 (m [AB], 2H), 4.20-4.33 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.54-3.62 (m, 1H), 3.44-3.53 (m, 1H)。
Embodiment 41
N-[1-(2-chloro-phenyl-)-2-hydroxyethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (non-enantiomer mixture)
Figure 198930DEST_PATH_IMAGE196
The compound of the embodiment 8A of 355 mg (0.97 mmol), the HOBt of the EDC of 223 mg (1.17 mmol) and 166 mg (1.17 mmol) at room temperature stirs 20 minutes in the DMF of 5 ml and the acetonitrile of 10 ml.This solution is added dropwise in the solution that the amino alcohol (200 mg, 1.17 mmol) of embodiment 66A forms in the acetonitrile of 10 ml, and mixture at room temperature reacts 30 minutes.Then add the 1N hydrochloric acid of 1 ml, preparation property HPLC purification (method 10) for complete reaction mixture.This obtains the title compound of 400 mg (theoretical value 77%).
LC-MS [method 3]: R t=1.15 min+1.16 min; MS in each situation [ESIpos]: m/z=519 (M+H) +
Separate two kinds of diastereomers by the preparation chromatography (method 17f) going up mutually in chirality: referring to embodiment 42 and 43.
Embodiment 42
N-[1-(2-chloro-phenyl-)-2-hydroxyethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer I)
Figure 551414DEST_PATH_IMAGE196
The first wash-out diastereomer (186 mg) being obtained from the separation of the compound of the embodiment 41 of 400 mg by method 17f.This product is also purified by preparation property HPLC (method 10), removes solvent residues.This obtains the title compound of 153 mg.
Analyze chirality HPLC [method 18b]: R t=5.30 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.75 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.46 (dd, 1H), 7.41 (dd, 1H), 7.25-7.36 (m, 2H), 6.89 (d, 1H), 5.24 (td, 1H), 5.09 (t, 1H), 4.48-4.60 (m [AB], 2H), 4.20-4.32 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.57-3.65 (m, 1H), 3.46-3.54 (m, 1H)。
Embodiment 43
N-[1-(2-chloro-phenyl-)-2-hydroxyethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer II)
Figure 304082DEST_PATH_IMAGE196
The last wash-out diastereomer (209 mg) being obtained from the separation of the compound of the embodiment 41 of 400 mg by method 17f.This product is also purified by preparation property HPLC (method 10), removes solvent residues.This obtains the title compound of 156 mg.
Analyze chirality HPLC [method 18b]: R t=6.94 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.74 (d, 1H), 7.75 (d, 2H), 7.63 (d, 2H), 7.46 (dd, 1H), 7.41 (dd, 1H), 7.24-7.36 (m, 2H), 6.91 (d, 1H), 5.25 (td, 1H), 5.09 (t, 1H), 4.54 (s, 2H), 4.22-4.32 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.57-3.65 (m, 1H), 3.45-3.54 (m, 1H)。
Embodiment 44
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{ (2R)-1-hydroxyl-2-[3-(trifluoromethyl) phenyl] propane-2-yl } ethanamide
Figure 804334DEST_PATH_IMAGE197
The compound of the embodiment 69A of the compound of the embodiment 8A of 151 mg (0.42 mmol) and 100 mg (0.46 mmol), the EDC of 119 mg (0.62 mmol) at room temperature stirs a night together with the HOBt of 84 mg (0.62 mmol) in the DMF of 4 ml, with the 1N mixed in hydrochloric acid of 1 ml, then purified completely by preparation property HPLC (method 10).This obtains the title compound of 91 mg (theoretical value 39%).
LC-MS [method 1] R t=2.04 min; MS [ESIpos]: m/z=567 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.33 (s, 1H), 7.74 (d, 2H), 7.60-7.66 (m, 4H), 7.48-7.57 (m, 2H), 6.89 (d, 1H), 5.12 (t, 1H), 4.48-4.60 (m [AB], 2H), 4.20-4.32 (m, 1H), 3.95 (dd, 1H), 3.81 (dd, 1H), 3.55-3.66 (m, 2H), 1.62 (s, 3H)。
Embodiment 45
Carboxylamine (2R)-2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] propyl diester
Figure 490530DEST_PATH_IMAGE198
The compound of the embodiment 71A of the compound of the embodiment 8A of 76 mg (0.21 mmol) and 75 mg (0.25 mmol), the EDC of 48 mg (0.25 mmol), be introduced in the DMF of 2 ml with together with the HOBt of 36 mg (0.25 mmol), add the N of 73 μ L (0.42 mmol), N-diisopropylethylamine, mixture at room temperature stirs a night.The 1N mixed in hydrochloric acid of it and 1 ml, then by preparation property HPLC fully purify (method 10).This obtains the title compound (theoretical value 58%) of 78 mg.
LC-MS [method 3] R t=1.23 min; MS [ESIpos]: m/z=610 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.58 (s, 1H), 7.74 (d, 2H), 7.69 (d, 1H), 7.57-7.66 (m, 4H), 7.54 (t, 1H), 6.87 (d, 1H), 6.40-6.75 (br.s, 2H), 4.50 (s, 2H), 4.22-4.32 (m, 1H), 4.22 (d, 1H), 4.16 (d, 1H), 3.95 (dd, 1H), 3.81 (dd, 1H), 1.68 (s, 3H)。
Embodiment 46
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl ester (non-enantiomer mixture)
Figure 510570DEST_PATH_IMAGE199
The compound of the embodiment 60A of the compound of the embodiment 8A of 599 mg (1.64 mmol) and 750 mg (1.96 mmol), the EDC of 377 mg (1.96 mmol) is introduced in the DMF of 20ml together with the HOBt of 279 mg (1.96 mmol), add the N of 570 μ L (3.27 mmol), N-diisopropylethylamine, mixture at room temperature stirs a night.The 1N mixed in hydrochloric acid of it and 5 ml, then by preparation property HPLC fully purify (method 10).This obtains the title compound (theoretical value 46%) of 450 mg.
LC-MS [method 5] R t=1.06 min; MS [ESIpos]: m/z=596 (M+H) +
Separate two kinds of diastereomers by the preparation chromatography (method 17a) going up mutually in chirality: referring to embodiment 47 and 48.
Embodiment 47
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl ester (diastereomer I)
Figure 624019DEST_PATH_IMAGE200
The first wash-out diastereomer (209 mg) being obtained from the separation of the compound of the embodiment 46 of 400 mg by method 17a.This product is also purified by preparation property HPLC (method 10), removes solvent residues.This obtains the title compound of 169 mg.
Analyze chirality HPLC [method 18a]: R t=7.44 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 8.88 (d, 1H), 7.70-7.78 (m, 3H), 7.56-7.70 (m, 5H), 6.92 (d, 1H), 6.39-6.79 (br.s, 2H), 5.12-5.20 (m, 1H), 4.45-4.60 (m [AB], 2H), 4.22-4.34 (m, 1H), 4.06-4.17 (m, 2H), 3.96 (dd, 1H), 3.83 (dd, 1H)。
Embodiment 48
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl ester (diastereomer II)
Figure 611567DEST_PATH_IMAGE201
The last wash-out diastereomer (190 mg) being obtained from the separation of the compound of the embodiment 46 of 450 mg by method 17a.This product is also purified by preparation property HPLC (method 10), removes solvent residues.This obtains the title compound of 167 mg.
Analyze chirality HPLC [method 18a]: R t=17.99 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.89 (d, 1H), 7.70-7.77 (m, 3H), 7.56-7.70 (m, 5H), 6.90 (d, 1H), 6.45-6.77 (br.s, 2H), 5.12-5.19 (m, 1H), 4.53 (s, 2H), 4.21-4.33 (m, 1H), 4.07-4.17 (m, 2H), 3.96 (dd, 1H), 3.83 (dd, 1H)。
Embodiment 49
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[2-(trifluoromethyl) phenyl] ethyl ester (non-enantiomer mixture)
The compound of the embodiment 8A of 428 mg (1.17 mmol) at room temperature stirs 10 minutes together with the EDC of 269 mg (1.41 mmol) and the HOBt of 200 mg (1.41 mmol) in the DMF of 10 ml and the acetonitrile of 40 ml.This solution is added dropwise in the compound of embodiment 63A of 400 mg (1.41 mmol) and solution that the DIPEA of 408 μ L (2.34 mmol) forms in the acetonitrile of 50 ml, and mixture at room temperature stirs a night.It then with the 1N mixed in hydrochloric acid of 1 ml, then by preparation property HPLC fully purify (method 10).This obtains the title compound (theoretical value 83%) of 580 mg.
LC-MS [method 2] R t=2.24 min; MS [ESIpos]: m/z=596 (M+H) +
Separate two kinds of diastereomers by the preparation chromatography (method 17d) going up mutually in chirality: referring to embodiment 50 and 51.
Embodiment 50
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[2-(trifluoromethyl) phenyl] ethyl ester (diastereomer I)
The first wash-out diastereomer (297 mg) being obtained from the separation of the compound of the embodiment 49 of 580 mg by method 17d.This product is also purified by preparation property HPLC (method 10), removes solvent residues.This obtains the title compound of 239 mg.
Analyze chirality HPLC [method 18c]: R t=3.26 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 8.97 (d, 1H), 7.68-7.78 (m, 5H), 7.62 (d, 2H), 7.52 (t, 1H), 6.92 (d, 1H), 6.40-6.81 (2 br. s, 2H), 5.36-5.44 (m, 1H), 4.49 (s, 2H), 4.21-4.33 (m, 1H), 4.13 (dd, 1H), 3.91-4.01 (m, 2H), 3.81 (dd, 1H)。
Embodiment 51
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[2-(trifluoromethyl) phenyl] ethyl ester (diastereomer II)
Figure 994772DEST_PATH_IMAGE202
The last wash-out diastereomer (280 mg) being obtained from the separation of the compound of the embodiment 49 of 580 mg by method 17d.Product is also with preparation property HPLC purification (method 10).This obtains the title compound of 222 mg.
Analyze chirality HPLC [method 18c]: R t=4.49 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 8.98 (d, 1H), 7.69-7.79 (m, 5H), 7.62 (d, 2H), 7.49-7.56 (m, 1H), 6.90 (d, 1H), 6.40-6.81 (2 br. s, 2H), 5.35-5.42 (m, 1H), 4.43-4.55 (m [AB], 2H), 4.19-4.32 (m, 1H), 4.13 (dd, 1H), 3.92-4.01 (m, 2H), 3.82 (dd, 1H)。
Embodiment 52
Carboxylamine (2R)-2-(3-chloro-phenyl-)-2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino] ethyl ester
Figure 469615DEST_PATH_IMAGE203
According to the method identical with embodiment 1, obtain the title compound (theoretical value 59%) of 183 mg from the compound of embodiment 8A of 203 mg (0.55 mmol) and the compound of the embodiment 65A of 153 mg (0.61 mmol).
LC-MS [method 3] R t=1.19 min; MS [ESIpos]: m/z=562 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.79 (d, 1H), 7.76 (d, 2H), 7.63 (d, 2H), 7.43 (s, 1H), 7.29-7.41 (m, 3H), 6.92 (d, 1H), 6.41-6.80 (2 br. s, 2H), 5.02-5.11 (m, 1H), 4.43-4.59 (m, 2H), 4.22-4.34 (m, 1H), 4.02-4.15 (m, 2H), 3.96 (dd, 1H), 3.83 (dd, 1H)。
Embodiment 53
Carboxylamine 2-(2-chloro-phenyl-)-2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino] ethyl ester (non-enantiomer mixture)
Figure 497614DEST_PATH_IMAGE204
The compound of the embodiment 8A of 606 mg (1.66 mmol) at room temperature stirs 10 minutes together with the EDC of 382 mg (1.99 mmol) and the HOBt of 283 mg (1.99 mmol) in the DMF of 5 ml and the acetonitrile of 10 ml.This solution is added dropwise to the compound of embodiment 68A and the N of 578 μ L (3.31 mmol) of 500 mg (1.99 mmol), in the solution that N-diisopropylethylamine forms in the acetonitrile of 10 ml, mixture further at room temperature stirs 30 minutes.The 1N mixed in hydrochloric acid of it and 1 ml, then by preparation property HPLC fully purify (method 10).This obtains the title compound (theoretical value 48%) of 446 mg.
LC-MS [method 5] R t=1.01 min; MS [ESIpos]: m/z=562 (M+H) +
Separate two kinds of diastereomers by the preparation chromatography (method 17f) going up mutually in chirality: referring to embodiment 54 and 55.
Embodiment 54
Carboxylamine 2-(2-chloro-phenyl-)-2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino] ethyl ester (diastereomer I)
Figure 492246DEST_PATH_IMAGE204
The last wash-out diastereomer (227 mg) being obtained from the separation of the compound of the embodiment 53 of 443 mg by method 17f.This product is also purified by preparation property HPLC (method 10), removes solvent residues.This obtains the title compound of 200 mg.
Analyze chirality HPLC [method 18b]: R t=1.77 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.92 (d, 1H), 7.75 (d, 2H), 7.63 (d, 2H), 7.51 (dd, 1H), 7.44 (dd, 1H), 7.29-7.40 (m, 2H), 6.92 (d, 1H), 6.43-6.80 (2 br.s, 2H), 5.40-5.47 (m, 1H), 4.45-4.57 (m [AB], 2H), 4.21-4.32 (m, 1H), 4.00-4.12 (m, 2H), 3.96 (dd, 1H), 3.82 (dd, 1H)。
Embodiment 55
Carboxylamine 2-(2-chloro-phenyl-)-2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino] ethyl ester (diastereomer II)
Figure 947498DEST_PATH_IMAGE204
The last wash-out diastereomer (231 mg) being obtained from the separation of the compound of the embodiment 53 of 443 mg by method 17f.This product is also purified by preparation property HPLC (method 10), removes solvent residues.This obtains the title compound of 202 mg.
Analyze chirality HPLC [method 18b]: R t=2.46 min
1H NMR (DMSO-d 6, 400 MHz): δ = 8.93 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.51 (dd, 1H), 7.45 (dd, 1H), 7.30-7.40 (m, 2H), 6.90 (d, 1H), 6.44-6.79 (2 br.s, 2H), 5.38-5.46 (m, 1H), 4.52 (s, 2H), 4.21-4.32 (m, 1H), 4.00-4.12 (m, 2H), 3.96 (dd, 1H), 3.82 (dd, 1H)。
Embodiment 56
Carboxylamine (2R)-2-(2-chloro-phenyl-)-2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino] propyl diester
Figure 581742DEST_PATH_IMAGE205
(approximately 90% is pure for the compound of the embodiment 8A of 42 mg (0.12 mmol) and 32 mg, 0.13 mmol) the compound of embodiment 75A, the EDC of 26 mg (0.14 mmol), the HOBt of 17 mg (0.14 mmol) at room temperature stirs 1 hour together in the DMF of 1.3 ml.Then mixture purifies completely by preparation property HPLC (method 10).This obtains the title compound (theoretical value 63%) of 42 mg.
LC-MS [method 4] R t=1.01 min; MS [ESIpos]: m/z=576 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.58 (s, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.46 (dd, 1H), 7.37 (dd, 1H), 7.22-7.32 (br. s, 2H), 6.89 (d, 1H), 6.45-6.75 (m, 2H), 4.45 (s, 2H), 4.36-4.44 (m, 2H), 4.20-4.33 (m, 1H), 3.93 (dd, 1H), 3.80 (dd, 1H), 1.74 (s, 3H)。
Embodiment 57
N-{2-(carbamido group)-1-[3-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer I)
Figure 210169DEST_PATH_IMAGE206
The compound of the embodiment 11 of 266 mg (0.45 mmol) is added in the methanol/water 1:1 of 6 ml, then with at room temperature blending of potassium cyanate (110 mg, 1.36 mmol).Mixture heats 90 minutes at 40 DEG C.After complete reaction, mixture is cooled to room temperature, is then purified completely by preparation property HPLC (method 10).The dry title compound that obtains 232 mg (theoretical value 84%) in HV.
LC-MS [method 4]: R t=1.02 min; MS [ESIpos]: m/z=595 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.78 (d, 1H), 7.76 (d, 2H), 7.54-7.66 (m, 6H), 6.94 (d, 1H), 6.09 (t, 1H), 5.60 (s, 2H), 4.87-4.95 (m, 1H), 4.49 (s, 2H), 4.25-4.38 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.29-3.38 (m, 1H), 3.19-3.27 (m, 1H)。
Embodiment 58
N-{2-(carbamido group)-1-[3-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer II)
Figure 327817DEST_PATH_IMAGE206
The compound of the embodiment 12 of 180 mg (0.31 mmol) is added in the methanol/water 1:1 of 3 ml, then with at room temperature blending of potassium cyanate (75 mg, 0.92 mmol).Mixture heats 90 minutes at 40 DEG C.On rotatory evaporator, remove methyl alcohol, the water dilution of 20 ml for water-based residue.The solid by filtration of precipitation is separated, with a small amount of water washing and dry in HV.This obtains the title compound of 146 mg (theoretical value 76%).
LC-MS [method 4]: R t=1.02 min; MS [ESIpos]: m/z=595 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.79 (d, 1H), 7.77 (d, 2H), 7.54-7.66 (m, 6H), 6.94 (d, 1H), 6.08 (t, 1H), 5.59 (s, 2H), 4.88-4.95 (m, 1H), 4.41-4.56 (m [AB], 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.84 (dd, 1H), 3.29-3.38 (m, 1H), 3.16-3.27 (m, 1H)。
Embodiment 59
N-{2-(carbamido group)-1-[2-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer I)
Figure 16287DEST_PATH_IMAGE207
According to the mode identical with embodiment 57, obtain title compound (190 mg, theoretical value 79%) from the compound of the embodiment 13 of 230mg (0.39 mmol).
LC-MS [method 3]: R t=1.17 min; MS [ESIpos]: m/z=595 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.84 (d, 1H), 7.77 (d, 2H), 7.62-7.74 (m, 5H), 7.48 (t, 1H), 6.95 (d, 1H), 6.22 (t, 1H), 5.58 (s, 2H), 5.06-5.13 (m, 1H), 4.39-4.51 (m [AB], 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.21-3.27 (m, 2H)。
Embodiment 60
N-{2-(carbamido group)-1-[2-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer II)
Figure 137827DEST_PATH_IMAGE207
According to the mode identical with embodiment 57, but at room temperature, obtain title compound (41 mg, theoretical value 81%) from the compound of the embodiment 14 of 50 mg (85 μ mol).
LC-MS [method 2]: R t=2.19 min; MS [ESIpos]: m/z=595 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.84 (d, 1H), 7.76 (d, 2H), 7.60-7.72 (m, 5H), 7.48 (t, 1H), 6.93 (d, 1H), 6.23 (t, 1H), 5.59 (s, 2H), 5.05-5.12 (m, 1H), 4.45 (s, 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.15-3.34 (m, 2H)。
Embodiment 61
N-[2-(carbamido group)-1-(2,3-dichlorophenyl) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer I)
Figure 320678DEST_PATH_IMAGE208
According to the mode identical with embodiment 57, obtain title compound (90 mg, theoretical value 77%) from the compound of the embodiment 15 of 116mg (0.20 mmol).
LC-MS [method 3]: R t=1.19 min; MS [ESIpos]: m/z=595 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.91 (d, 1H), 7.77 (d, 2H), 7.63 (d, 2H), 7.52-7.59 (m, 1H), 7.34-7.40 (m, 2H), 6.94 (d, 1H), 6.19 (t, 1H), 5.60 (s, 2H), 5.12-5.20 (m, 1H), 4.40-4.55 (q [AB], 2H), 4.25-4.37 (m, 1H), 3.97 (dd, 1H), 3.84 (dd, 1H), 3.28-3.37 (m, 1H), 3.19-3.28 (m, 1H)。
Embodiment 62
N-[2-(carbamido group)-1-(2,3-dichlorophenyl) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer II)
Figure 476852DEST_PATH_IMAGE208
According to the mode identical with embodiment 57, obtain title compound (153 mg, theoretical value 85%) from the compound of the embodiment 16 of 177mg (0.30 mmol).
LC-MS [method 3]: R t=1.20 min; MS [ESIpos]: m/z=595 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.91 (d, 1H), 7.76 (d, 2H), 7.63 (d, 2H), 7.52-7.59 (m, 1H), 7.34-7.40 (m, 2H), 6.94 (d, 1H), 6.19 (t, 1H), 5.61 (s, 2H), 5.12-5.19 (m, 1H), 4.48 (s, 2H), 4.26-4.38 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.29-3.38 (m, 1H), 3.18-3.27 (m, 1H)。
Embodiment 63
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(1E)-3; 3; 3-trifluoropropyl-1-alkene-1-yl]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl ester (racemoid)
Figure 336224DEST_PATH_IMAGE209
The compound of the embodiment 77A of 100 mg (0.29 mmol) is joined in the DMF of 3 ml, then with the compound of the embodiment 60A of 98.3 mg (0.35 mmol), the EDC of 66.1 mg (0.35 mmol), the DIPEA blending of the HOBt of 49 mg (0.35 mmol) and 75 μ L (0.43 mmol).Mixture at room temperature stirs 30 minutes, with the 1N mixed in hydrochloric acid of 1 ml, then by preparation property HPLC purification (method 10).This obtains the title compound of 140 mg (theoretical value 84%).
LC/MS [method 5]: R t=1.16 min; M/z=578 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 8.90 (d, 1H), 7.73 (s, 1H), 7.57-7.69 (m, 7H), 7.18 (dq, 1H), 6.87 (dq, 1H), 5.09-5.27 (m, 1H), 4.47-4.68 (m [AB], 2H), 3.99-4.21 (m, 2H)。
Separate the enantiomer of embodiment 63 by the preparation chromatography (method 15b) going up mutually in chirality: referring to embodiment 64 and embodiment 65.
Embodiment 64
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(1E)-3; 3; 3-trifluoropropyl-1-alkene-1-yl]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl ester (enantiomer I)
Figure 758109DEST_PATH_IMAGE209
The first wash-out enantiomer (64 mg) being obtained from the separation of the compound of the embodiment 63 of 135 mg by method 15b.
Analyze chirality HPLC [method 16]: R t=1.50 min.
Embodiment 65
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(1E)-3; 3; 3-trifluoropropyl-1-alkene-1-yl]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl ester (enantiomer II)
Figure 728339DEST_PATH_IMAGE209
The last wash-out enantiomer (62 mg) being obtained from the separation of the compound of the embodiment 63 of 135 mg by method 15b.
Analyze chirality HPLC [method 16]: R t=1.90 min.
Embodiment 66
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{3-hydroxyl-1-[3-(trifluoromethyl) phenyl] propyl group } ethanamide (non-enantiomer mixture)
Figure 739021DEST_PATH_IMAGE210
According to the method identical with embodiment 24, obtain title compound from the compound of embodiment 8A of 100 mg (0.27 mmol) and the compound of the embodiment 78A of 84 mg (0.33 mmol): 112 mg (theoretical value 72%).
LC-MS [method 3] R t=1.22 min; MS [ESIpos]: m/z=567 (M+H) +
Separate the diastereomer of embodiment 66 by the preparation chromatography (method 8) going up mutually in chirality: referring to embodiment 67 and embodiment 68.
Embodiment 67
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{3-hydroxyl-1-[3-(trifluoromethyl) phenyl] propyl group } ethanamide (diastereomer I)
The first wash-out diastereomer (50 mg) being obtained from the chromatographic separation of the compound of the embodiment 66 of 112 mg by method 8.
Analyze chirality HPLC [method 9]: R t=3.25 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 8.71 (d, 1H), 7.73 (dd, 2H), 7.54-7.66 (m, 6H), 6.90 (d, 1H), 4.97-5.05 (m, 1H), 4.58 (t, 1H), 4.42-4.56 (m [AB], 2H), 4.21-4.33 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.32-3.47 (m, 2H), 1.77-1.96 (m, 2H)。
Embodiment 68
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{3-hydroxyl-1-[3-(trifluoromethyl) phenyl] propyl group } ethanamide (diastereomer II)
Figure 616158DEST_PATH_IMAGE210
The last wash-out diastereomer (47 mg) being obtained from the chromatographic separation of the compound of the embodiment 66 of 112 mg by method 8.
Analyze chirality HPLC [method 9]: R t=4.41 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 8.70 (d, 1H), 7.74 (dd, 2H), 7.53-7.66 (m, 6H), 6.92 (d, 1H), 4.98-5.08 (m, 1H), 4.59 (t, 1H), 4.49 (s, 2H), 4.21-4.33 (m, 1H), 3.95 (dd, 1H), 3.82 (dd, 1H), 3.32-3.47 (m, 2H), 1.77-1.96 (m, 2H)。
Embodiment 69
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{ (1S)-3-hydroxyl-1-[2-(trifluoromethyl) phenyl] propyl group } ethanamide
Figure 327762DEST_PATH_IMAGE211
According to the method identical with embodiment 49, obtain title compound from the compound of embodiment 8A of 167 mg (0.46 mmol) and the compound of the embodiment 80A of 140 mg (0.55 mmol): 152 mg (theoretical value 58%).
LC-MS [method 3] R t=1.21 min; MS [ESIpos]: m/z=567 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.75 (d, 1H), 7.74 (d, 2H), 7.64-7.70 (m, 3H), 7.62 (d, 2H), 7.41-7.50 (m, 1H), 6.90 (d, 1H), 5.20-5.28 (m, 1H), 4.57 (t, 1H), 4.40-4.55 (m [AB], 2H), 4.21-4.32 (m, 1H), 3.95 (dd, 1H), 3.81 (dd, 1H), 3.41-3.56 (m, 2H), 1.69-1.87 (m, 2H)。
Embodiment 70
Carboxylamine (3S)-3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-3-[2-(trifluoromethyl) phenyl] propyl diester
According to the method identical with embodiment 49, obtain title compound from the compound of embodiment 8A of 194 mg (0.53 mmol) and the compound of the embodiment 81A of 190 mg (0.64 mmol): 138 mg (theoretical value 43%).
LC-MS [method 5] R t=1.04 min; MS [ESIpos]: m/z=610 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.84 (d, 1H), 7.65-7.76 (m, 5H), 7.62 (d, 2H), 7.42-7.51 (m, 1H), 6.90 (d, 1H), 6.33-6.58 (br. s, 2H), 5.20-5.28 (m, 1H), 4.57 (t, 1H), 4.42-4.59 (m [AB], 2H), 4.01-4.08 (m, 1H), 3.86-3.99 (m, 2H), 3.82 (dd, 1H), 1.83-1.99 (m, 2H)。
Embodiment 71
Carboxylamine 3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl } ethanoyl) amino]-3-(2,3-dichlorophenyl) propyl diester (non-enantiomer mixture)
Figure 394124DEST_PATH_IMAGE213
According to the method identical with embodiment 1, obtain title compound from the compound of embodiment 8A of 630 mg (1.72 mmol) and the compound of the embodiment 88A of 568 mg (1.90 mmol): 809 mg (theoretical value 77%).
LC-MS [method 3] R t=1.22+1.23 min; MS [ESIpos]: m/z=610 (M+H) +
Separate the diastereomer of embodiment 71 by the preparation chromatography (method 13) going up mutually in chirality: referring to embodiment 72 and embodiment 73.
Embodiment 72
Carboxylamine 3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl } ethanoyl) amino]-3-(2,3-dichlorophenyl) propyl diester (diastereomer I)
Figure 787672DEST_PATH_IMAGE214
The first wash-out diastereomer (270 mg) being obtained from the chromatographic separation of the compound of the embodiment 71 of 800 mg by method 13.
LC-MS [method 5] R t=1.07 min; MS [ESIpos]: m/z=610 (M+H) +
Analyze chirality HPLC [method 14]: R t=5.61 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 8.83-8.90 (m, 1H), 7.75 (d, 2H), 7.63 (d, 2H), 7.54 (d, 1H), 7.44 (dd, 1H), 7.37 (t, 1H), 6.91 (d, 1H), 6.32-6.70 (br. s, 2H), 5.25-5.33 (m, 1H), 4.47-4.60 (m [AB], 2H), 4.20-4.34 (m, 1H), 3.88-4.04 (m, 3H), 3.82 (dd, 1H), 1.83-2.02 (m, 2H)。
Embodiment 73
Carboxylamine 3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl } ethanoyl) amino]-3-(2,3-dichlorophenyl) propyl diester (diastereomer II)
The last wash-out diastereomer (270 mg) being obtained from the chromatographic separation of the compound of the embodiment 71 of 800 mg by method 13.
LC-MS [method 5] R t=1.07 min; MS [ESIpos]: m/z=610 (M+H) +
Analyze chirality HPLC [method 14]: R t=14.96 min.
1H NMR (DMSO-d 6, 400 MHz): δ = 8.87 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.55 (dd, 1H), 7.44 (dd, 1H), 7.38 (t, 1H), 6.90 (d, 1H), 6.34-6.69 (br.s, 2H), 5.24-5.32 (m, 1H), 4.44-4.62 (m [AB], 2H), 4.21-4.32 (m, 1H), 3.88-4.05 (m, 3H), 3.82 (dd, 1H), 1.83-2.02 (m, 2H)。
Embodiment 74
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[(1R)-1-(2,3-3,5-dimethylphenyl)-2-hydroxyethyl] ethanamide
Figure 84978DEST_PATH_IMAGE215
The compound of the embodiment 8A of 50 mg (0.14 mmol), the EDC of 39 mg (0.21 mmol) at room temperature stirs 20 minutes together with the HOBt of 28 mg (0.21 mmol) in the DMF of 1.2 ml, then with (2R)-2-amino-2-(2 of 30 mg, 3-3,5-dimethylphenyl) N of ethylate hydrochlorate (0.15 mmol) and 31 μ L (0.18 mmol), N-diisopropylamine mixes.Mixture at room temperature stirs 2 hours.Subsequently, preparation property HPLC purification (method 10) for complete reaction mixture.This obtains the title compound of 58 mg (theoretical value 81%).
LC-MS [method 5]: R t=1.04 min; M/z=513 (M+H) +
1H NMR (DMSO-d 6,400 MHz): δ = 8.60 (d, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.16 (dd, 1H), 7.01-7.08 (m, 2H), 6.89 (d, 1H), 5.08-5.16 (m, 1H), 4.94 (t, 1H), 4.41-4.56 (m [AB], 2H), 4.21-4.32 (m, 1H), 3.96 (dd, 1H), 3.82 (dd, 1H), 3.41-3.56 (m, 2H), 2.23 (s, 3H), 2.20 (s, 3H)。
Embodiment 75
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[(1R)-1-(3-cyano-phenyl)-2-hydroxyethyl] ethanamide
Figure 394736DEST_PATH_IMAGE216
According to the mode identical with embodiment 74, obtain the title compound of 42 mg (theoretical value 60%) from the compound (0.14 mmol) of embodiment 8A of 50 mg and (2R)-2-amino-2-(3-cyano-phenyl) ethylate hydrochlorate (0.15 mmol) of 30 mg.
LC-MS [method 5]: R t=0.95 min; M/z=510 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.68 (d, 1H), 7.79 (s, 1H), 7.70-7.77 (m, 3H), 7.68 (d, 1H), 7.62 (d, 2H), 7.54 (t, 1H), 6.90 (d, 1H), 5.03 (t, 1H), 4.87-4.94 (m, 1H), 4.56 (s, 2H), 4.22-4.33 (m, 1H), 3.97 (dd, 1H), 3.83 (dd, 1H), 3.58-3.64 (m, 2H)。
Embodiment 76
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[(1R)-1-(3-chloro-phenyl-)-2-hydroxyethyl] ethanamide
Figure 278510DEST_PATH_IMAGE217
According to the mode identical with embodiment 74, obtain the title compound of 54 mg (theoretical value 76%) from the compound (0.14 mmol) of embodiment 8A of 50 mg and (2R)-2-amino-2-(3-chloro-phenyl-) ethylate hydrochlorate (0.15 mmol) of 31 mg.
LC-MS [method 5]: R t=1.03 min; M/z=519 (M+H) +
1H NMR (DMSO-d 6,400 MHz): δ = 8.62 (d, 1H), 7.76 (d, 2H), 7.62 (d, 2H), 7.39 (s, 1H), 7.26-7.38 (m, 3H), 6.92 (d, 1H), 5.00 (t, 1H), 4.82-4.90 (m, 1H), 4.47-4.59 (m [AB], 2H), 4.21-4.35 (m, 1H), 3.96 (dd, 1H), 3.83 (dd, 1H), 3.55-3.63 (m, 2H)。
Embodiment 77
N-[(2R)-2-(2-chloro-phenyl-)-1-hydroxyl third-2-yl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide
Figure 394233DEST_PATH_IMAGE218
According to the mode identical with embodiment 1, obtain the title compound of 33 mg (theoretical value 36%) from the compound (0.17 mmol) of embodiment 8A of 62 mg and the compound (0.19 mmol) of the embodiment 74A of 49 mg.
LC-MS [method 4]: R t=1.02 min; M/z=533 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.27 (s, 1H), 7.74 (d, 2H), 7.62 (d, 2H), 7.47 (dd, 1H), 7.33 (dd, 1H), 7.18-7.28 (m, 2H), 6.89 (d, 1H), 5.11 (t, 1H), 4.48 (s, 2H), 4.19-4.33 (m, 1H), 3.86-3.97 (m, 2H), 3.73-3.85 (m, 2H), 1.68 (s, 3H)。
Embodiment 78
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{3, the fluoro-2-hydroxyl-1-[3-of 3,3-tri-(trifluoromethyl) phenyl] propyl group } ethanamide (non-enantiomer mixture)
Figure 234013DEST_PATH_IMAGE219
The compound of the embodiment 8A of 113 mg (0.31 mmol), the amino alcohol of the embodiment 99A of 93 mg (0.34 mmol), the EDC of 83 mg (0.43 mmol) at room temperature stirs 2 hours together with the HOBt of 59 mg (0.43 mmol) in the DMF of 4.3 ml.Subsequently, preparation property HPLC purification (method 10) for reaction mixture.This obtains the title compound of 162 mg (theoretical value 80%), is the mixture of 4 kinds of diastereomers.
LC-MS [method 5]: R t=1.14 min; MS [ESIpos]: m/z=621 (M+H) +
1H NMR (DMSO-d 6, 400 MHz): δ = 8.97 + 8.93 + 8.92 (3x d, 1H), 7.86 + 7.81 (2x s, 1H), 7.55-7.77 (m, 7H), 6.82-6.93 (5x d, 1.4H), 6.72 (d, 0.6H), 5.41 (br d, 0.4H), 5.15-5.21 (m, 0.6H), 4.42-4.66 (m, 2H), 4.20-4.40 (m, 2H), 3.92-4.01 (br d, 1H), 3.77-3.87 (2x dd, 1H)。
Embodiment 79
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[1-(2,3-dichlorophenyl)-3-hydroxypropyl] ethanamide (non-enantiomer mixture)
Figure 714673DEST_PATH_IMAGE220
The compound of the embodiment 8A of 100 mg (0.27 mmol) is dissolved in the DMF of 4 ml, mix with the EDC of 68 mg (0.36 mmol) with the HOBt of 44 mg (0.33 mmol), then at room temperature stir 10 minutes.The compound that adds subsequently the embodiment 90A of 66 mg (0.30 mmol), mixture at room temperature stirs 16 hours.For aftertreatment, add the water of 10 ml, the ethyl acetate extracting twice of 10 ml for mixture.The organic phase dried over sodium sulfate merging, filters and concentrates on rotatory evaporator.Preparation property HPLC purification [method 19] for crude product.This obtains the target compound of 44 mg (theoretical value 28%).
LC-MS [method 3] R t=1.24 min; MS [ESIpos]: m/z=567/569/571 (M+H) +
By the preparation chromatography (method 11d) going up mutually in chirality, the non-enantiomer mixture of embodiment 79 is separated into diastereomer: referring to embodiment 80 and embodiment 81.
Embodiment 80
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[1-(2,3-dichlorophenyl)-3-hydroxypropyl] ethanamide (diastereomer I)
The first wash-out diastereomer obtaining from the separation of embodiment 79.
Output: 21 mg (theoretical value 14%)
R t=4.04 min [method 12c]
LC-MS [method 5] R t=1.07 min; MS [ESIpos]: m/z=567/569/571 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 1.92-2.03 (m, 1H), 2.04-2.15 (m, 1H), 3.02 (br.s, 1H), 3.55-3.66 (m, 1H), 3.68-3.78 (m, 1H), 3.93-4.05 (m, 2H), 4.47-4.60 (m, 2H), 4.70 (d, 1H), 5.26 (d, 1H), 5.49 (td, 1H), 7.15-7.23 (m, 1H), 7.27-7.31 (m, 1H), 7.35-7.42 (m, 1H), 7.50 (d, 2H), 7.57-7.71 (m, 3H)。
Embodiment 81
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[1-(2,3-dichlorophenyl)-3-hydroxypropyl] ethanamide (diastereomer II)
Figure 677261DEST_PATH_IMAGE220
The last wash-out diastereomer obtaining from the separation of embodiment 79.
Output: 20 mg (theoretical value 13%).
R t=4.84 min [method 12c]
LC-MS [method 5] Rt=1.07 min; MS [ESIpos]: m/z=567 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 1.88-2.00 (m, 1H), 2.04-2.15 (m, 1H), 3.05 (br.s, 1H), 3.54-3.68 (m, 1H), 3.70-3.81 (m, 1H), 3.91-4.06 (m, 2H), 4.51 (d, 1H), 4.54-4.62 (m, 1H), 4.69 (d, 1H), 5.22 (d, 1H), 5.49 (td, 1H), 7.10-7.23 (m, 2H), 7.37 (dd, 1H), 7.45 (d, 1H), 7.52 (d, 2H), 7.65 (d, 2H)。
Embodiment 82
N-[1-(2-chloro-phenyl-)-3-hydroxypropyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (non-enantiomer mixture)
Figure 433865DEST_PATH_IMAGE221
The compound of the embodiment 8A of 100 mg (0.27 mmol) is dissolved in the DMF of 1 ml, mixes with the EDC of 79 mg (0.41 mmol) and the HOBt of 55 mg (0.41 mmol), then at room temperature stir 10 minutes.Add subsequently 3-amino-3-(2-chloro-phenyl-) propane-1-alcohol hydrochloride of 67 mg (0.30 mmol) and the DIPEA of 63 μ L (0.38 mmol), mixture at room temperature stirs 16 hours.For aftertreatment, add the water of 10 ml, the ethyl acetate extracting twice of 10 ml for mixture.The organic phase dried over mgso merging, filters and concentrates on rotatory evaporator.Preparation property HPLC purification [method 19] for crude product.This obtains the target compound of 93 mg (theoretical value 64%).
LC-MS [method 3] R t=1.16 min; MS [ESIpos]: m/z=533/535 (M+H) +
By the preparation chromatography (method 8a) going up mutually in chirality, the non-enantiomer mixture of embodiment 82 is separated into diastereomer: referring to embodiment 83 and embodiment 84.
Embodiment 83
N-[1-(2-chloro-phenyl-)-3-hydroxypropyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer I)
Figure 351005DEST_PATH_IMAGE221
The first wash-out diastereomer obtaining from the separation of embodiment 82.
Output: 34 mg (theoretical value 23%).
R t=2.00 min [method 14]
LC-MS [method 6] R t=2.21 min; MS [ESIpos]: m/z=533/535 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 1.93-2.15 (m, 2H), 3.26 (br.s, 1H), 3.57-3.67 (m, 1H), 3.68-3.77 (m, 1H), 3.89-4.05 (m, 2H), 4.48-4.62 (m, 2H), 4.72 (d, 1H), 5.36-5.45 (m, 1H), 5.49 (td, 1H), 7.17-7.25 (m, 1H), 7.35 (d, 2H), 7.49 (d, 2H), 7.57 (d, 1H), 7.64 (d, 2H)。
Embodiment 84
N-[1-(2-chloro-phenyl-)-3-hydroxypropyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer II)
Figure 130742DEST_PATH_IMAGE221
The last wash-out diastereomer obtaining from the separation of embodiment 82.
Output: 38 mg (theoretical value 26%).
R t=2.92 min [method 14]
LC-MS [method 1] R t=1.86 min; MS [ESIpos]: m/z=533/535 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 1.90-2.15 (m, 2H), 3.56-3.68 (m, 1H), 3.69-3.79 (m, 1H), 3.87-4.06 (m, 2H), 4.50 (d, 1H), 4.53-4.63 (m, 1H), 4.70 (d, 1H), 5.48 (td, 1H), 7.16-7.23 (m, 2H), 7.30-7.40 (m, 2H), 7.51 (d, 2H), 7.65 (d, 2H)。
Embodiment 85
2-[3-(4-chloro-phenyl-)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[1-(2-chloro-phenyl-)-3-hydroxypropyl] ethanamide (racemoid)
According to the mode same with the Compound Phase of embodiment 82, [3-(4-chloro-phenyl-)-4-cyclopropyl-5-oxo-4 of 30 mg (0.10 mmol), 5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid (for preparation referring to WO 2007/134862, embodiment 88A) react.This obtains the target compound of 14 mg (theoretical value 30%).
LC-MS [method 3] R t=1.12min; MS [ESIpos]: m/z=461/463 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 0.67-0.79 (m, 2H), 0.97-1.09 (m, 2H), 1.92-2.15 (m, 2H), 2.67 (br.s, 1H), 2.99 (tt, 1H), 3.57-3.79 (m, 2H), 4.45-4.65 (m, 2H), 5.51 (td, 1H), 7.17-7.25 (m, 2H), 7.30-7.39 (m, 2H), 7.47 (d, 2H), 7.68 (d, 2H)。
Embodiment 86
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[3-hydroxyl-1-(2-aminomethyl phenyl) propyl group] ethanamide (non-enantiomer mixture)
Figure 215690DEST_PATH_IMAGE223
The compound of the embodiment 8A of 250 mg (0.68 mmol) is dissolved in the DMF of 5 ml, mix with the EDC of 170 mg (0.89 mmol) with the HOBt of 111 mg (0.82 mmol), then at room temperature stir 10 minutes.3-amino-3-(2-aminomethyl phenyl) propane-1-alcohol that adds subsequently 124 mg (0.75 mmol), mixture at room temperature stirs 16 hours.For aftertreatment, add the water of 10 ml, the ethyl acetate extracting twice of 10 ml for mixture.The organic phase dried over sodium sulfate merging, filters and concentrates on rotatory evaporator.Preparation property HPLC purification [method 19] for crude product.This obtains the target compound of 181 mg (theoretical value 52%).
LC-MS [method 1] R t=1.84 and 1.86 min; MS [ESIpos]: m/z=513 (M+H) +
By the preparation chromatography (method 8a) going up mutually in chirality, the non-enantiomer mixture of embodiment 86 is separated into diastereomer: referring to embodiment 87 and embodiment 88.
Embodiment 87
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[3-hydroxyl-1-(2-aminomethyl phenyl) propyl group] ethanamide (diastereomer I)
The first wash-out diastereomer obtaining from the separation of embodiment 86.
Output: 86 mg (theoretical value 25%).
R t=1.80 min [method 14]
LC-MS [method 6] R t=2.19 min; MS [ESIpos]: m/z=513 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 1.65-1.91 (m, 2H), 2.32 (s, 3H), 3.33-3.48 (m, 2H), 3.81 (dd, 1H), 3.95 (dd, 1H), 4.20-4.34 (m, 1H), 4.35-4.57 (m, 3H), 5.06-5.18 (m, 1H), 6.90 (d, 1H), 7.11 (d, 2H), 7.14-7.21 (m, 1H), 7.31 (d, 1H), 7.62 (d, 2H), 7.74 (d, 2H), 8.59 (d, 1H)。
Embodiment 88
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[3-hydroxyl-1-(2-aminomethyl phenyl) propyl group] ethanamide (diastereomer II)
Figure 109446DEST_PATH_IMAGE223
The last wash-out diastereomer obtaining from the separation of embodiment 86.
Output: 87 mg (theoretical value 25%).
R t=2.76 min [method 14]
LC-MS [method 6] R t=2.21 min; MS [ESIpos]: m/z=513 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 1.68-1.89 (m, 2H), 2.32 (s, 3H), 3.34-3.49 (m, 2H), 3.82 (dd, 1H), 3.95 (dd, 1H), 4.20-4.33 (m, 1H), 4.45 (dd, 2H), 4.53 (t, 1H), 5.08-5.18 (m, 1H), 6.91 (d, 1H), 7.11 (d, 2H), 7.14-7.20 (m, 1H), 7.31 (d, 1H), 7.59-7.65 (m, 2H), 7.74 (d, 2H), 8.58 (d, 1H)。
Embodiment 89
2-[3-(4-chloro-phenyl-)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[3-hydroxyl-1-(3-p-methoxy-phenyl) propyl group] ethanamide (racemoid)
Figure 308346DEST_PATH_IMAGE224
According to the mode same with the Compound Phase of embodiment 86, [3-(4-chloro-phenyl-)-4-cyclopropyl-5-oxo-4 of 30 mg (0.10 mmol), 5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid (for preparation referring to WO 2007/134862, embodiment 88A) and 3-amino-3-(3-p-methoxy-phenyl) propane-1-alcohol of 20 mg (0.11 mmol) react.This obtains the target compound of 30 mg (theoretical value 63%).
LC-MS [method 3] R t=1.08 min; MS [ESIpos]: m/z=456 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 0.69-0.80 (m, 2H), 0.97-1.08 (m, 2H), 1.78-1.90 (m, 1H), 2.05-2.17 (m, 1H), 2.86 (br.s, 1H), 2.98 (tt, 1H), 3.57-3.74 (m, 2H), 3.77 (s, 3H), 4.55 (q, 2H), 5.20 (td, 1H), 6.75-6.84 (m, 2H), 6.87 (d, 1H), 7.04 (d, 1H), 7.21-7.25 (m, 1H), 7.46 (d, 2H), 7.67 (d, 2H)。
Embodiment 90
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-(3, the fluoro-1-phenyl propyl of 3,3-tri-) ethanamide (non-enantiomer mixture)
Figure 977225DEST_PATH_IMAGE225
According to the mode same with the Compound Phase of embodiment 86,3,3 of the compound of the embodiment 8A of 50 mg (0.14 mmol) and 28 mg (0.15 mmol), the fluoro-1-phenyl of 3-tri-third-1-amine reacts.This obtains the target compound of 44 mg (theoretical value 59%).
LC-MS [method 3] R t=1.30 min; MS [ESIpos]: m/z=537 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 2.53-2.81 (m, 2H), 3.92-4.07 (m, 2H), 4.43-4.67 (m, 4H), 5.28-5.37 (m, 1H), 6.70 (dd, 1H), 7.27-7.40 (m, 5H), 7.46-7.56 (m, 4H)。
Embodiment 91
N-[1-(3-chloro-phenyl-)-3-hydroxypropyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (non-enantiomer mixture)
Figure 32906DEST_PATH_IMAGE226
According to the Compound Phase of embodiment 79 with mode, obtain the title compound of 48 mg (theoretical value 65%) from the compound of embodiment 8A of 50 mg (0.14 mmol) and 3-amino-3-(3-chloro-phenyl-) propane-1-alcohol of 28 mg (0.15 mmol).
LC-MS [method 1] R t=1.89 and 1.90 min; MS [ESIpos]: m/z=533 (M+H) +
1h-NMR (400 MHz, CDCl 3): δ=1.78-1.91 (m, 1H), 2.00-2.15 (m, 1H), 3.14 (br.s, 0.5H), 3.25 (br.s, 0.5H), 3.54-3.74 (m, 2H), 3.89-4.06 (m, 2H), 4.43-4.74 (m, 3H), 5.10-5.22 (m, 1H), 5.28-5.40 (m, 1H), 7.10-7.30 (m, 4.5H), 7.42 (d, 0.5H), 7.46-7.53 (m, 2H), 7.64 (m, 2H) (part of the signal of dual group of non-enantiomer mixture splits).
Embodiment 92
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[1-(2-fluorophenyl)-3-hydroxypropyl] ethanamide (non-enantiomer mixture)
Figure 600284DEST_PATH_IMAGE227
The compound of the embodiment 93A of 39 mg (0.07 mmol) is dissolved in to 1 of 2 ml, in 2-glycol dimethyl ether, gained solution at room temperature uses the sodium borohydride of 4.1 mg (0.11 mmol) and the lithium chloride of 0.6 mg (0.014 mmol) to mix in succession.Then mixture stirs 16 hours at 85 DEG C.For aftertreatment, add the saturated soluble tartrate sodium water solution of 10 ml, mixture extracts three times by the ethyl acetate of 10 ml.The organic phase dried over mgso merging, filters and concentrates on rotatory evaporator.Preparation property HPLC purification [method 19] for crude product.This obtains the target compound of 19 mg (theoretical value 49%).
LC-MS [method 6] R t=2.13 min; MS [ESIpos]: m/z=517 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 1.92-2.11 (m, 2H), 3.55-3.76 (m, 2H), 3.89-4.07 (m, 2H), 4.43-4.77 (m, 3H), 5.31-5.44 (m, 1H), 6.98-7.15 (m, 2H), 7.17-7.39 (m, 2H), 7.46-7.54 (m, 2H), 7.59-7.68 (m, 2H)。
Embodiment 93
Carboxylamine 3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-3-(2-fluorophenyl) propyl diester (non-enantiomer mixture)
Figure 337296DEST_PATH_IMAGE228
The compound of the embodiment 8A of 354 mg (0.97 mmol) is dissolved in the DMF of 3 ml, mix with the EDC of 260 mg (1.36 mmol) with the HOBt of 183 mg (1.36 mmol), then at room temperature stir 10 minutes.The compound of embodiment 89A and the DIPEA of 192 μ L (1.16 mmol) that add subsequently 265 mg (1.07 mmol), mixture at room temperature stirs 2 hours.For aftertreatment, it dilutes with the DMF of 5 ml, and crude product is directly by preparation property HPLC[method 19] purify.This obtains the target compound of 420 mg (theoretical value 77%).
LC-MS [method 5] R t=0.99 min; MS [ESIpos]: m/z=560 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 1.74-2.09 (m, 2H), 3.36-3.47 (m, 1H), 3.72-4.03 (m, 3H), 4.19-4.36 (m, 1H), 4.38-4.60 (m, 2H), 5.10-5.25 (m, 1H), 6.50 (br.s, 2H), 6.86-6.95 (m, 1H), 7.09-7.23 (m, 2H), 7.24-7.36 (m, 1H), 7.36-7.46 (m, 1H), 7.56-7.67 (m, 2H), 7.69-7.78 (m, 2H), 8.57-8.77 (m, 1H)。
Embodiment 94
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-(3, the fluoro-2-hydroxyl-1-of 3,3-tri-phenyl propyl) ethanamide (non-enantiomer mixture)
According to the mode same with the Compound Phase of embodiment 93,3-amino-1 of the compound of the embodiment 8A of 100 mg (0.27 mmol) and 73 mg (0.30 mmol), the fluoro-3-phenyl of 1,1-tri-propan-2-ol hydrochloride reacts.This obtains the target compound of 102 mg (theoretical value 63%), is non-enantiomer mixture.
LC-MS [method 2] R t=2.29 min; MS [ESIpos]: m/z=552 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 3.88-4.07 (m, 2H), 4.15-4.26 (m, 1H), 4.42-4.75 (m, 5H), 4.97-5.09 (m, 1H), 5.37 (dd, 1H), 7.15-7.41 (m, 5H), 7.44-7.53 (m, 2H), 7.56-7.65 (m, 2H)。
Embodiment 95
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[1-(2,3-difluorophenyl)-2-hydroxyethyl] ethanamide (non-enantiomer mixture)
The compound of the embodiment 8A of 128 mg (0.27 mmol) is dissolved in the DMF of 1 ml, mix with the EDC of 83 mg (0.43 mmol) with the HOBt of 58 mg (0.43 mmol), then at room temperature stir 10 minutes.The compound of embodiment 92A and the triethylamine of 51 μ L (0.37 mmol) that add subsequently 79 mg (0.37 mmol), mixture at room temperature stirs 16 hours.For aftertreatment, add the water of 10 ml, the ethyl acetate extracting twice of 10 ml for mixture.The organic phase dried over sodium sulfate merging, filters and concentrates on rotatory evaporator.Preparation property HPLC purification [method 19] for crude product.This obtains the target compound of 118 mg (theoretical value 68%).
LC-MS [method 4] R t=0.99 min; MS [ESIpos]: m/z=521 (M+H) +
1h-NMR (400 MHz, CDCl 3): δ=3.13-3.25 (m, H), 3.45-3.52 (m, H), 3.58-3.70 (m, H), 3.74-3.83 (m, H), 3.83-4.10 (m, H), 4.46-4.57 (m, H), 4.58-4.78 (m, H), 5.25 (d, H), 5.29-5.40 (m, H), 5.62 (d, H), 6.95 (d, H), 6.99-7.16 (m, H), 7.48 (dd, H), 7.54 (d, H), 7.62 (d, H), 7.68 (d, H) (part of the signal of dual group of non-enantiomer mixture splits.)。
embodiment 96
2-[3-(4-chloro-phenyl-)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{2-hydroxyl-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (racemoid)
Figure 594468DEST_PATH_IMAGE231
According to the mode same with the Compound Phase of embodiment 95, [3-(4-chloro-phenyl-)-4-cyclopropyl-5-oxo-4 of 48 mg (0.16 mmol), 5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid (for preparation referring to WO 2007/134862, embodiment 88A) and the compound of the embodiment 91A of 58 mg (0.18 mmol) react.This obtains the target compound of 61 mg (theoretical value 77%).
LC-MS [method 4] R t=1.02 min; MS [ESIpos]: m/z=481 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ = 0.72-0.82 (m, 2H), 0.99-1.09 (m, 2H), 2.36-2.45 (m, 1H), 3.00 (spt, 1H), 3.83-4.00 (m, 2H), 4.53-4.67 (m, 2H), 5.13-5.20 (m, 1H), 7.43-7.50 (m, 3H), 7.50-7.58 (m, 3H), 7.69 (d, 2H)。
Embodiment 97
2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine methyl ester (non-enantiomer mixture)
Figure 682641DEST_PATH_IMAGE232
The compound of the embodiment 8A of 393 mg (1.07 mmol), the compound of the embodiment 138A of 353 mg (1.18 mmol), the EDC of 247 mg (1.29 mmol), the DIPEA of the HOBt of 174 mg (1.29 mmol) and 225 μ L (1.29 mmol) at room temperature stirs 1 hour in the DMF of 13 ml.Preparation property HPLC[method 23 for whole reaction soln] purify.Suitable fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 416 mg (theoretical value 64%), is non-enantiomer mixture (according to analyzing HPLC[method 22] ratio 20:78).
LC-MS [method 5] R t=1.09 min; MS [ESIpos]: m/z=610 (M+H) +
By the preparation HPLC[method 21a going up mutually in chirality] separate two kinds of diastereomers: referring to embodiment 98 and embodiment 99.
Embodiment 98
2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine methyl ester (diastereomer I)
Figure 326112DEST_PATH_IMAGE232
The first wash-out diastereomer (51 mg, d.e. > 99.5%) obtaining from the chromatographic separation [method 21a] of the compound of the embodiment 97 of 416 mg.
Chiral analysis HPLC [method 22]: R t=3.52 min.
LC-MS [method 4] R t=1.11 min; MS [ESIpos]: m/z=610 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.22-3.40 (m, 2H), 3.47 (s, 3 H), 3.83 (dd, 1H), 3.96(dd, 1H), 4.22-4.35 (m, 1H), 4.51 (s, 2H), 5.02 (q, 1 H), 6.91 (d, 1 H), 7.26 (t, 1 H), 7.54-7.65 (m, 5H), 7.66 (s, 1H), 7.75 (d, 2H), 8.68 (d, 1H)。
Embodiment 99
2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine methyl ester (diastereomer II)
Figure 661278DEST_PATH_IMAGE232
The last wash-out diastereomer being obtained from the chromatographic separation of the compound of the embodiment 97 of 416 mg by method 21a.Products therefrom (238 mg, d.e.> 99.5%) is further purified by preparation property HPLC [method 20].This obtains the title compound of 180 mg.
Chiral analysis HPLC [method 22]: R t=4.81 min.
LC-MS [method 5] R t=1.11 min; MS [ESIpos]: m/z=610 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.23-3.39 (m, 2H), 3.47 (s, 3 H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.21-4.33 (m, 1H), 4.44-4.57 (m, 2H [AB]), 5.01 (q, 1 H), 6.88 (d, 1 H), 7.26 (t, 1 H), 7.53-7.65 (m, 5H), 7.67 (s, 1H), 7.74 (d, 2H), 8.69 (d, 1H)。
Embodiment 100
2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine ethyl ester (non-enantiomer mixture)
Figure 452517DEST_PATH_IMAGE233
The compound of the embodiment 8A of 465 mg (1.27 mmol), the compound of the embodiment 137A of 437 mg (1.40 mmol), the EDC of 292 mg (1.52 mmol), the N of the HOBt of 206 mg (1.52 mmol) and 266 μ L (1.52 mmol), N '-diisopropylethylamine at room temperature stirs 1 hour in the DMF of 15 ml.Preparation property HPLC[method 23 for whole solution] purify.Suitable fraction desolvation on rotatory evaporator, residue is dry in HV.The title compound that this obtains 524 mg (theoretical value 66%), is non-enantiomer mixture (ratio 23:74).
LC-MS [method 5] R t=1.15 min; MS [ESIpos]: m/z=624 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 21a going up mutually in chirality] separate: referring to embodiment 101 and embodiment 102.
Embodiment 101
2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine ethyl ester (diastereomer I)
Figure 531331DEST_PATH_IMAGE233
The first wash-out diastereomer (109 mg) being obtained from the chromatographic separation of the compound of the embodiment 100 of 520 mg by method 21a.
Chiral analysis HPLC [method 22]: R t=3.42 min.
LC-MS [method 5] R t=1.15 min; MS [ESIpos]: m/z=624 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 1.08 (t, 3H), 3.23-3.40 (m, 2H), 3.79-3.99 (m, 4H), 4.22-4.33 (m, 1H), 4.51 (s, 2H), 5.02 (q, 1H), 6.91 (d, 1H), 7.21 (t, 1H), 7.53-7.68 (m, 6H), 7.75 (d, 2H), 8.68 (d, 1H)。
Embodiment 102
2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl } carboxylamine ethyl ester (diastereomer II)
Figure 842358DEST_PATH_IMAGE234
The last wash-out diastereomer being obtained from the chromatographic separation of the compound of the embodiment 100 of 520 mg by method 21a.Products therefrom (356 mg) is further purified by preparation property HPLC [method 20].This obtains the title compound of 297 mg.
Chiral analysis HPLC [method 22]: R t=4.31 min.
LC-MS [method 5] R t=1.15 min; MS [ESIpos]: m/z=624 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 1.08 (t, 3H), 3.23-3.37 (m, 2H), 3.28-4.01 (m, 4H), 4.22-4.33 (m, 1H), 4.42-4.60 (m[AB], 2H), 5.01 (q, 1H), 6.88 (d, 1H), 7.21 (t, 1H), 7.50-7.68 (m, 6H), 7.73 (d, 2H), 8.69 (d, 1H)。
Embodiment 103
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(ethylamino formyl radical) amino]-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 614005DEST_PATH_IMAGE235
The compound of the embodiment 8A of 483 mg (1.32 mmol), the compound of the embodiment 139A of 453 mg (1.45 mmol), the EDC of 304 mg (1.59 mmol), the DIPEA of the HOBt of 214 mg (1.59 mmol) and 276 μ L (1.59 mmol) at room temperature stirs a night in the DMF of 15.5 ml.Because reaction is incomplete, add EDC, HOBt and each 0.8 mmol of DIPEA, mixture further stirs 1 hour.Preparation property HPLC[method 23 for whole solution] purify.Suitable fraction desolvation on rotatory evaporator, residue is dry in HV.The title compound that this obtains 428 mg (theoretical value 52%), is non-enantiomer mixture (according to the ratio 3.5:1 of NMR).
LC-MS [method 4] R t=1.09 min; MS [ESIpos]: m/z=623 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 13a going up mutually in chirality] separate: referring to embodiment 104 and embodiment 105.
Embodiment 104
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(ethylamino formyl radical) amino]-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 626960DEST_PATH_IMAGE235
The first wash-out diastereomer (333 mg) being obtained from the chromatographic separation of the compound of the embodiment 103 of 428 mg by method 13a.
Chiral analysis HPLC [method 14]: R t=1.62 min.
1H NMR (400 MHz, DMSO-d 6): δ = 0.92 (t, 3H), 2.88-3.00 (m, 2 H), 3.21-3.39 (m, 2H), 3.82 (dd, 1H), 3.97 (dd, 1H), 4.24-4.38 (m, 1H), 4.44-4.54 (m[AB], 2H), 4.87-4.98 (m, 1H), 5.95 (q, 2H), 6.91 (d, 1H), 7.53-7.66 (m, 6H), 7.76 (d, 2H), 8.79 (d, 1H)。
Embodiment 105
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-[(ethylamino formyl radical) amino]-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 509466DEST_PATH_IMAGE235
The last wash-out diastereomer (100 mg) being obtained from the chromatographic separation of the compound of the embodiment 103 of 428 mg by method 13a.
Chiral analysis HPLC [method 14]: R t=2.60 min.
1H NMR (400 MHz, DMSO-d6): δ = 0.91 (t, 3H), 2.83-3.00 (m, 2 H), 3.20-3.38 (m, 2H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.27-4.39 (m, 1H), 4.41-4.51 (m [AB], 2H), 4.89-4.96 (m, 1H), 5.95 (q, 2H), 6.95 (d, 1H), 7.54-7.66 (m, 6H), 7.77 (d, 2H), 8.79 (d, 1H)。
Embodiment 106
N-[2-(carbamido group)-1-(2-chloro-phenyl-) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (non-enantiomer mixture)
Figure 861950DEST_PATH_IMAGE236
The compound of the embodiment 8A of 311 mg (0.85 mmol), the compound of the embodiment 143A of 279 mg (0.94 mmol), the EDC of 245 mg (1.28 mmol), the DIPEA of the HOBt of 173 mg (1.28 mmol) and 193 μ L (1.11 mmol) at room temperature stirs 2 hours in the DMF of 8 ml.Preparation property HPLC[method 10 for whole solution] purify.Suitable fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 182 mg (theoretical value 36%), is non-enantiomer mixture.
LC-MS [method 4] R t=0.97 and 0.98 min; MS [ESIpos]: m/z=561 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 17d going up mutually in chirality] separate: referring to embodiment 107 and embodiment 108.
Embodiment 107
N-[2-(carbamido group)-1-(2-chloro-phenyl-) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer I)
Figure 614617DEST_PATH_IMAGE237
The first wash-out diastereomer being obtained from the chromatographic separation of the compound of the embodiment 106 of 120 mg by method 17d.Products therefrom is further purified by preparation property HPLC [method 10].This obtains the title compound of 40 mg.
Chiral analysis HPLC [method 18b]: R t=1.81 min.
LC-MS [method 3] Rt=1.12 min; MS [ESIpos]: m/z=561 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.15-3.25 (m, 1H), 3.26-3.36 (m, 1H), 3.84 (dd, 1H), 3.98 (dd, 1H), 4.24-4.37 (m, 1H), 4.39-4.55 (m[AB], 2H), 5.09-5.18 (m, 1H), 5.58 (s, 2H), 6.17 (t, 1H), 6.95 (d, 1H), 7.25-7.37 (m, 2H), 7.39-7.45 (m, 2H), 7.63 (d, 2H), 7.77 (d, 2H), 8.81 (d, 1H)。
Embodiment 108
N-[2-(carbamido group)-1-(2-chloro-phenyl-) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (diastereomer II)
The last wash-out diastereomer being obtained from the chromatographic separation of the compound of the embodiment 106 of 120 mg by method 17d.Products therefrom (51 mg) is further purified by preparation property HPLC [method 10].This obtains the title compound of 40 mg.
Chiral analysis HPLC [method 18b]: R t=2.77 min.
LC-MS [method 3] Rt=1.13 min; MS [ESIpos]: m/z=561 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.15-3.25 (m, 1H), 3.26-3.36 (m, 1H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.26-4.38 (m, 1H), 4.42-4.53 (m [AB], 2H), 5.09-5.17 (m, 1H), 5.59 (s, 2H), 6.18 (t, 1H), 6.95 (d, 1H), 7.25-7.37 (m, 2H), 7.38-7.45 (m, 2H), 7.63 (d, 2H), 7.77 (d, 2H), 8.81 (d, 1H)。
Embodiment 109
Carboxylamine 3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-3-[3-(trifluoromethyl) phenyl] propyl diester (non-enantiomer mixture)
The compound of the embodiment 8A of 945 mg (2.59 mmol), the HOBt of the EDC of 743 mg (3.88 mmol) and 552 mg (3.88 mmol) at room temperature stirs 20 minutes in the DMF of 25 ml.Gained solution is added dropwise in the solution being formed in the acetonitrile of 75 ml by the compound of the embodiment 129A of 678 mg (2.59 mmol).After at room temperature 30 minutes, on rotatory evaporator, remove acetonitrile.The 1M mixed in hydrochloric acid of remaining solution and 1 ml, then by preparation property HPLC[method 10] purify.Suitable fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 1.18 g (theoretical value 75%).
LC-MS [method 2] R t=2.27 min; MS [ESIpos]: m/z=610 (M+H) +
By the preparation HPLC[method 15a going up mutually in chirality] from two kinds of diastereomers of gained compound separation of 180 mg: referring to embodiment 110 and embodiment 111.
Embodiment 110
Carboxylamine 3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-3-[3-(trifluoromethyl) phenyl] propyl diester (diastereomer I)
Figure 8056DEST_PATH_IMAGE239
The first wash-out diastereomer being obtained from the separation of the compound of the embodiment 109 of 180 mg by method 15a.The product separating is further purified by preparation property HPLC [method 10].This obtains the title compound of 81 mg.
Chiral analysis HPLC [method 16]: R t=2.40 min
LC-MS [method 5] R t=1.07 min; MS [ESIpos]: m/z=610 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 1.91-2.07 (m, 2H), 3.77-3.87 (m, 2H), 3.88-3.99 (m, 2H), 4.22-4.35 (m, 1H), 4.50 (s, 2H), 4.95-5.04 (m, 1H), 6.51 (br. s., 2H), 6.93 (d, 1H), 7.55-7.68 (m, 6H), 7.71-7.78 (m, 2H), 8.78 (d, 1H)。
Embodiment 111
Carboxylamine 3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-3-[3-(trifluoromethyl) phenyl] propyl diester (diastereomer II)
Figure 934554DEST_PATH_IMAGE240
The last wash-out diastereomer being obtained from the separation of the compound of the embodiment 109 of 180 mg by method 15a.The product separating is further purified by preparation property HPLC [method 10].This obtains the title compound of 68 mg.
Chiral analysis HPLC [method 16]: R t=3.28 min.
LC-MS [method 4] R t=1.05 min; MS [ESIpos]: m/z=610 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 1.90-2.07 (m, 2H), 3.76-4.03 (m, 4H), 4.20-4.34 (m, 1H), 4.41-4.60 (m [AB], 2H), 4.93-5.05 (m, 1H), 6.52 (br. s., 2H), 6.91 (d, 1H), 7.55-7.68 (m, 6H), 7.74 (d, 2H), 8.79 (d, 1H)。
Embodiment 112
Carboxylamine 2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3; 3,3-trifluoro propyl)-4,5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-[3-(trifluoromethyl) phenyl] ethyl ester (enantiomer-pure)
Figure 859785DEST_PATH_IMAGE241
The compound of the embodiment 65 of 250 mg (0.43 mmol) in the methyl alcohol of 37 ml at platinum (5%, 104 mg on carbon) one night of at room temperature hydrogenation in atmosphere of hydrogen (pressure=1 is atmospheric).Subsequent filtration is removed catalyzer, and filtrate is used preparation property HPLC purification [method 20].This obtains the title compound of 161 mg (theoretical value 64%).
LC-MS [method 2] R t=2.34 min; MS [ESIpos]: m/z=580 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.56-2.69 (m, 2H), 3.98 (t, 2H), 4.03-4.20 (m, 2H), 4.43-4.59 (m [AB], 2H), 5.06-5.22 (m, 1H), 6.57 (br. s., 2H), 7.55-7.75 (m, 8H), 8.85 (d, 1H)。
Embodiment 113
[2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4; 5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-(2,3-dichlorophenyl) ethyl] carboxylamine methyl ester (racemoid)
Figure 84093DEST_PATH_IMAGE242
The compound of the embodiment 177A of 144 mg (0.41 mmol), the compound of the embodiment 151A of 136 mg (0.45 mmol), the EDC of 94 mg (0.50 mmol), the DIPEA of the HOBt of 67 mg (0.50 mmol) and 86 μ L (0.50 mmol) at room temperature stirs 1 hour in the DMF of 4.9 ml.Preparation property HPLC[method 20 for whole solution] purify.Suitable fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 173 mg (theoretical value 70%).
LC-MS [method 5] R t=1.15 min; MS [ESIpos]: m/z=594 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.54-2.68 (m, 2H), 3.21-3.36 (m, 2H), 3.50 (s, 3H), 3.98 (t, 2H), 4.44-4.56 (m [AB], 2H), 5.31 (q, 1H), 7.31 (br. t, 1H), 7.36 (t, 1H), 7.45 (dd, 1 H), 7.56 (dd, 1H), 7.61-7.69 (m, 4H), 8.67 (d, 1H)。
Two kinds of enantiomers are by the preparation HPLC[method 21b going up mutually in chirality] separate: referring to embodiment 114 and embodiment 115.
Embodiment 114
[2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4; 5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-(2,3-dichlorophenyl) ethyl] carboxylamine methyl ester (enantiomer 1)
Figure 207907DEST_PATH_IMAGE242
The first wash-out enantiomer (77 mg) being obtained from the enantiomer chromatographic separation of the compound of the embodiment 113 of 173 mg by method 21b.The product obtaining is further purified by preparation property HPLC [method 20].In HV, the dry title compound that obtains 62 mg, is white solid.
Chiral analysis HPLC [method 22]: R t=6.48 min.
Embodiment 115
[2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4; 5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-(2,3-dichlorophenyl) ethyl] amino first methyl acid esters (enantiomer 2)
Figure 492258DEST_PATH_IMAGE242
The last wash-out enantiomer (71 mg) being obtained from the enantiomer chromatographic separation of the compound of the embodiment 113 of 173 mg by method 21b.The product obtaining is further purified by preparation property HPLC [method 20].In HV, the dry title compound that obtains 60 mg, is white solid.
Chiral analysis HPLC [method 22]: R t=11.02 min.
Embodiment 116
[2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4; 5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-(2,3-dichlorophenyl) ethyl] carboxylamine ethyl ester (racemoid)
Figure 717834DEST_PATH_IMAGE243
The compound of the embodiment 177A of 155 mg (0.44 mmol), the compound of the embodiment 152A of 153 mg (0.49 mmol), the EDC of 102 mg (0.53 mmol), the N of the HOBt of 72 mg (0.53 mmol) and 93 μ L (0.53 mmol), N '-diisopropylethylamine at room temperature stirs 1 hour in the DMF of 5 ml.Preparation property HPLC[method 20 for reaction soln] purify.Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 168 mg (theoretical value 62%).
LC-MS [method 5] R t=1.20 min; MS [ESIpos]: m/z=608 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 1.11 (t, 3H), 2.53-2.69 (m, 2H), 3.21-3.35 (m, 1H), 3.89-4.01 (m, 4H), 4.44-4.57 (m [AB], 2H), 5.31 (br. q, 1H), 7.26 (br. t, 1H), 7.36 (t, 1H), 7.44 (dd, 1H), 7.55 (dd, 1H), 7.60-7.68 (m, 4H), 8.67 (d, 1H)。
Two kinds of enantiomers are by the preparation HPLC[method 21b going up mutually in chirality] separate: referring to embodiment 117 and embodiment 118.
Embodiment 117
[2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4; 5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-(2,3-dichlorophenyl) ethyl] carboxylamine ethyl ester (enantiomer 1)
Figure 745833DEST_PATH_IMAGE244
The first wash-out enantiomer (67 mg) being obtained from the enantiomer chromatographic separation of the compound of the embodiment 116 of 168 mg by method 21b.The product obtaining is further purified by preparation property HPLC [method 20].In HV, the dry title compound that obtains 54 mg, is white solid.
Chiral analysis HPLC [method 22]: R t=5.36 min.
Embodiment 118
[2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4; 5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-(2,3-dichlorophenyl) ethyl] carboxylamine ethyl ester (enantiomer 2)
Figure 927415DEST_PATH_IMAGE244
The last wash-out enantiomer (71 mg) being obtained from the enantiomer chromatographic separation of the compound of the embodiment 116 of 168 mg by method 21b.The product obtaining is further purified by preparation property HPLC [method 20].In HV, the dry title compound that obtains 60 mg, is white solid.
Chiral analysis HPLC [method 22]: R t=9.85 min.
Embodiment 119
N-[2-(carbamido group)-1-(2,3-dichlorophenyl) ethyl]-2-[3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl] ethanamide (racemoid)
Figure 179405DEST_PATH_IMAGE245
The compound of the embodiment 177A of 162 mg (0.46 mmol), the compound of the embodiment 153A of 145 mg (0.51 mmol), the EDC of 107 mg (0.56 mmol), the N of the HOBt of 75 mg (0.56 mmol) and 97 μ L (0.56 mmol), N '-diisopropylethylamine at room temperature stirs a night in the DMF of 5.4 ml.The ethyl acetate dilution of 150 ml for solution, then uses 1M hydrochloric acid and 1M sodium bicarbonate aqueous solution extracting twice separately in succession.Organic phase dried over sodium sulfate is then removed volatile constituent on rotatory evaporator.Preparation property HPLC[method 20 for residue] purify.Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 163 mg (theoretical value 61%).
LC-MS [method 5] R t=1.04 min; MS [ESIpos]: m/z=579 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.56-2.72 (m, 2H), 3.17-3.37 (m, 2H), 3.98 (t, 2H), 4.40-4.52 (m [AB], 2H), 5.11-5.18 (m, 1H), 5.56 (s, 2H), 6.14 (t, 1H), 7.32-7.39 (m, 2H), 7.52-7.57 (m, 1H), 7.61-7.66 (m, 2H), 7.66-7.71 (m, 2H), 8.93 (d, 1H)。
Two kinds of enantiomers are by the preparation HPLC[method 24a going up mutually in chirality] separate: referring to embodiment 120 and embodiment 121.
Embodiment 120
N-[2-(carbamido group)-1-(2,3-dichlorophenyl) ethyl]-2-[3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl] ethanamide (enantiomer 1)
Figure 79228DEST_PATH_IMAGE245
The first wash-out enantiomer (61 mg) being obtained from the enantiomer chromatographic separation of the compound of the embodiment 119 of 160 mg by method 24a.The product obtaining is further purified by preparation property HPLC [method 20].The dry title compound that obtains 34 mg in HV.
Chiral analysis HPLC [method 25a]: R t=4.28 min.
Embodiment 121
N-[2-(carbamido group)-1-(2,3-dichlorophenyl) ethyl]-2-[3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl] ethanamide (enantiomer 2)
Figure 458388DEST_PATH_IMAGE245
The last wash-out enantiomer (81 mg) being obtained from the enantiomer chromatographic separation of the compound of the embodiment 119 of 160 mg by method 24a.The product obtaining is further purified by preparation property HPLC [method 20].The dry title compound that obtains 39 mg in HV.
Chiral analysis HPLC [method 25a]: R t=9.50 min.
Embodiment 122
2-[3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4; 5-dihydro-1H-1; 2,4-triazol-1-yl]-N-{1-(2,3-dichlorophenyl)-2-[(ethylamino formyl radical) amino] ethyl } ethanamide (racemoid)
Figure 760056DEST_PATH_IMAGE246
The compound of the embodiment 177A of 145 mg (0.42 mmol), the compound of the embodiment 154A of 143 mg (0.46 mmol), the EDC of 96 mg (0.50 mmol), the N of the HOBt of 67 mg (0.50 mmol) and 87 μ L (0.50 mmol), N '-diisopropylethylamine at room temperature stirs 1 hour in the DMF of 4.9 ml.Preparation property HPLC[method 20 for whole solution] purify.Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 150 mg (theoretical value 58%).
LC-MS [method 5] R t=1.12 min; MS [ESIpos]: m/z=607 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 0.92 (t, 3H), 2.57-2.71 (m, 2H), 2.86-2.99 (m, 2H), 3.19-3.38 (m, 2H), 3.98 (t, 2 H), 4.40-4.53 (m [AB], 2H), 5.13-5.20 (m, 1H), 5.93 (t, 1H), 6.02 (t, 1H), 7.32-7.39 (m, 2H), 7.50-7.58 (m, 1H), 7.61-7.72 (m, 4H), 8.91 (d, 1H)。
Two kinds of enantiomers are by the preparation HPLC[method 24b going up mutually in chirality] separate: referring to embodiment 123 and embodiment 124.
Embodiment 123
2-[3-(4-chloro-phenyl-)-5-oxo-4-(3; 3; 3-trifluoro propyl)-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl]-N-{1-(2,3-dichlorophenyl)-2-[(ethylamino formyl radical) amino] ethyl } ethanamide (enantiomer 1)
Figure 120630DEST_PATH_IMAGE246
The first wash-out enantiomer being obtained from the enantiomer chromatographic separation of the compound of the embodiment 122 of 160 mg by method 24b.The product obtaining is further purified by preparation property HPLC [method 20].The dry title compound that obtains 55 mg in HV.
Chiral analysis HPLC [method 25b]: R t=4.69 min.
Embodiment 124
2-[3-(4-chloro-phenyl-)-5-oxo-4-(3; 3; 3-trifluoro propyl)-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl]-N-{1-(2,3-dichlorophenyl)-2-[(ethylamino formyl radical) amino] ethyl } ethanamide (enantiomer 2)
Figure 570066DEST_PATH_IMAGE246
The last wash-out enantiomer being obtained from the enantiomer chromatographic separation of the compound of the embodiment 122 of 160 mg by method 24b.The product obtaining is further purified by preparation property HPLC [method 20].The dry title compound that obtains 51 mg in HV.
Chiral analysis HPLC [method 25b]: R t=9.41 min.
Embodiment 125
N-{1-(2-chloro-phenyl-)-2-[(methyl sulphonyl) amino] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanamide (non-enantiomer mixture)
Figure 939868DEST_PATH_IMAGE247
The compound of the embodiment 8A of 298 mg (0.81 mmol), the compound of the embodiment 144A of 304mg (0.90 mmol), the EDC of 234 mg (1.22 mmol), the N of the HOBt of 165 mg (1.22mmol) and 184 μ L (1.06mmol), N '-diisopropylethylamine at room temperature stirs 2 hours in the DMF of 7.7 ml.Preparation property HPLC[method 10 for whole solution] purify.Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 448 mg (theoretical value 90%).
LC-MS [method 4] R t=1.02 min; MS [ESIpos]: m/z=596 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 17h going up mutually in chirality] separate: referring to embodiment 126 and embodiment 127.
Embodiment 126
N-{1-(2-chloro-phenyl-)-2-[(methyl sulphonyl) amino] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanamide (diastereomer I)
Figure 646442DEST_PATH_IMAGE248
The first wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 125 of 440 mg by method 17h.The product obtaining is further purified by preparation property HPLC [method 20].The dry title compound that obtains 141 mg in HV.
Chiral analysis HPLC [method 18e]: R t=2.81 min.
LC-MS [method 4] R t=1.01 min; MS [ESIpos]: m/z=596 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.87 (s, 3H), 3.11-3.20 (m, 1H), 3.25-3.35 (m, 1H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.22-4.34 (m, 1H), 4.46-4.64 (m[AB], 2H), 5.31-5.39 (m, 1H), 6.85 (d, 1H), 7.28-7.40 (m, 3H), 7.44 (d, 1 H), 7.54 (d, 1 H), 7.61 (d, 2H), 7.74 (d, 2H), 8.66 (d, 1H)。
Embodiment 127
N-{1-(2-chloro-phenyl-)-2-[(methyl sulphonyl) amino] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanamide (diastereomer II)
The last wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 125 of 440 mg by method 17h.The product obtaining is further purified by preparation property HPLC [method 20].The dry title compound that obtains 102 mg in HV.
Chiral analysis HPLC [method 18e]: R t=4.14 min.
LC-MS [method 2] R t=2.20 min; MS [ESIpos]: m/z=596 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.88 (s, 3H), 3.11-3.19 (m, 1H), 3.25-3.33 (m, 1H), 3.83 (dd, 1H), 3.96 (br d, 1H), 4.23-4.34 (m, 1H), 4.55 (q, 2H), 5.32-5.40 (m, 1H), 6.88 (d, 1H), 7.29-7.34 (br t, 2H), 7.37 (t, 1H), 7.44 (d, 1H), 7.54 (d, 1H), 7.62 (d, 2H), 7.75 (d, 2H), 8.65 (d, 1H)。
Embodiment 128
N-{1-(2-chloro-phenyl-)-2-[(ethylsulfonyl) amino] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanamide (non-enantiomer mixture)
The compound of the embodiment 8A of 241 mg (0.66 mmol), the compound of the embodiment 145A of 249mg (0.74 mmol), the EDC of 189 mg (0.99 mmol), the N of the HOBt of 133 mg (0.99mmol) and 149 μ L (0.99mmol), N '-diisopropylethylamine at room temperature stirs 2 hours in the DMF of 6.2 ml.Preparation property HPLC[method 10 for whole solution] purify.Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 375 mg (theoretical value 91%).
LC-MS [method 4] R t=1.05 min; MS [ESIpos]: m/z=610 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 17g going up mutually in chirality] separate: referring to embodiment 129 and embodiment 130.
Embodiment 129
N-{1-(2-chloro-phenyl-)-2-[(ethylsulfonyl) amino] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanamide (diastereomer I)
Figure 288142DEST_PATH_IMAGE250
The first wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 128 of 370 mg by method 17g.The product obtaining is further purified by preparation property HPLC [method 20].In HV, the dry title compound that obtains 96 mg, is white solid.
Chiral analysis HPLC [method 18d]: R t=3.87 min.
LC-MS [method 4] R t=1.04 min; MS [ESIpos]: m/z=610 (M+H) +
1h NMR (400 MHz, DMSO-d 6): δ=1.15 (t, 3H), 2.88-3.02 (m, 2H), 3.11-3.19 (m, 1H), 3.24-3.33 (m, 1H, be hidden under water signal), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.22-4.33 (m, 1H), 4.49 (d, 1H), 4.60 (d, 1H), 5.28-5.37 (m, 1H), 6.85 (d, 1H), 7.29-7.40 (m, 3H), 7.44 (d, 1H), 7.53 (d, 1H), 7.61 (d, 2H), 7.74 (d, 2H), 8.64 (d, 1H).
Embodiment 130
N-{1-(2-chloro-phenyl-)-2-[(ethylsulfonyl) amino] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanamide (diastereomer II)
The last wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 128 of 370 mg by method 17g.The product obtaining is further purified by preparation property HPLC [method 20].The dry title compound that obtains 134 mg in HV.
Chiral analysis HPLC [method 18d]: R t=5.08 min.
LC-MS [method 4] R t=1.05 min; MS [ESIpos]: m/z=610 (M+H) +
1h NMR (400 MHz, DMSO-d 6): δ=1.16 (t, 3H), 2.90-3.02 (m, 2H), 3.10-3.19 (m, 1H), 3.24-3.33 (m, 1H, be hidden under water signal), 3.83 (dd, 1H), 3.96 (br d, 1H), 4.23-4.34 (m, 1H), 4.48-4.61 (m [AB], 2H), 5.30-5.37 (m, 1H), 6.88 (d, 1H), 7.28-7.39 (m, 3H), 7.43 (d, 1H), 7.53 (d, 1H), 7.62 (d, 2H), 7.75 (d, 2H), 8.62 (d, 1H).
Embodiment 131
N-[1-(2-chloro-phenyl-)-2-(methyl sulphonyl) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanamide (non-enantiomer mixture)
Figure 79829DEST_PATH_IMAGE252
The compound of the embodiment 8A of 327 mg (0.89 mmol), the compound of the embodiment 146A of 266 mg (0.98 mmol), the EDC of 206 mg (1.07 mmol), the N of the HOBt of 145 mg (1.07mmol) and 187 μ L (1.07 mmol), N '-diisopropylethylamine at room temperature stirs 1 hour in the DMF of 10.5 ml.Preparation property HPLC[method 20 for whole solution] purify.Suitable fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 354 mg (theoretical value 68%).
LC-MS [method 3] R t=1.16 min; MS [ESIpos]: m/z=581 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 26a going up mutually in chirality] separate: referring to embodiment 132 and embodiment 133.
Embodiment 132
N-[1-(2-chloro-phenyl-)-2-(methyl sulphonyl) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanamide (diastereomer I)
The first wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 131 of 354 mg by method 26a.Products therefrom (163 mg) is further purified by preparation property HPLC [method 20].The dry title compound that obtains 116 mg in HV.
Chiral analysis HPLC [method 27a]: R t=4.06 min.
LC-MS [method 5] R t=1.03 min; MS [ESIpos]: m/z=581 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.02 (s, 3H), 3.42 (m, 1H), 3.62 (dd, 1H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.33 (m, 1H), 4.51 (s, 2H), 5.72-5.80 (m, 1H), 6.89 (d, 1H), 7.31-7.42 (m, 2H), 7.47 (dd, 1H), 7.55 (dd, 1H), 7.60-7.65(m, 2H), 7.71-7.77 (m, 2H), 9.03 (d, 1H)。
Embodiment 133
N-[1-(2-chloro-phenyl-)-2-(methyl sulphonyl) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanamide (diastereomer II)
Figure 887565DEST_PATH_IMAGE253
The last wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 131 of 354 mg by method 26a.The product obtaining is further purified by preparation property HPLC [method 20].The dry title compound that obtains 131 mg in HV.
Chiral analysis HPLC [method 27a]: R t=4.71 min.
LC-MS [method 5] R t=1.03 min; MS [ESIpos]: m/z=581 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.02 (s, 3H), 3.42 (m, 1H), 3.62 (dd, 1H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.21-4.35 (m, 1H), 4.46-4.57 (m [AB], 2H), 5.74-5.81 (m, 1H), 6.91 (d, 1H), 7.31-7.42 (m, 2H), 7.46 (dd, 1H), 7.56 (dd, 1H), 7.60-7.66 (m, 2H), 7.72-7.78 (m, 2H), 9.03 (d, 1H)。
Embodiment 134
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-(methyl sulphonyl)-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 815070DEST_PATH_IMAGE254
The compound of the embodiment 8A of 438mg (1.20 mmol), the compound of the embodiment 148A of 400 mg (1.32 mmol), the EDC of 275 mg (1.44 mmol), the N of the HOBt of 194 mg (1.44mmol) and 250 μ L (1.44 mmol), N '-diisopropylethylamine at room temperature stirs 1 hour in the DMF of 10.5 ml.Preparation property HPLC[method 20 for whole solution] purify.Suitable fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 594 mg (theoretical value 79%).
LC-MS [method 3] R t=1.19 min; MS [ESIpos]: m/z=615 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 11e going up mutually in chirality] separate: referring to embodiment 135 and embodiment 136.
Embodiment 135
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-(methyl sulphonyl)-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
The first wash-out diastereomer (245 mg) being obtained from the diastereomer chromatographic separation of the compound of the embodiment 134 of 594 mg by method 11e.The product obtaining mixes with the acetonitrile of 10 ml and the water of 20 ml, then freeze-drying.
Chiral analysis HPLC [method 12a]: R t=5.11 min.
LC-MS [method 4] R t=1.04 min; MS [ESIpos]: m/z=615 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.01 (s, 3H), 3.36 (dd, 1H), 3.67 (dd, 1H), 3.82 (dd, 1H), 3.95 (dd, 1H), 4.21-4.33 (m, 1H), 4.48 (s, 2H), 5.74-5.84 (m, 1H), 6.92 (d, 1H), 7.53 (t, 1H), 7.59-7.65 (m, 2H), 7.70-7.82 (m, 5H), 9.08 (d, 1H)。
Embodiment 136
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-(methyl sulphonyl)-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 350404DEST_PATH_IMAGE256
The last wash-out diastereomer (225 mg) being obtained from the diastereomer chromatographic separation of the compound of the embodiment 134 of 594 mg by method 11e.The product obtaining mixes with the acetonitrile of 10 ml and the water of 20 ml, then freeze-drying.
Chiral analysis HPLC [method 12a]: R t=8.30 min.
LC-MS [method 4] R t=1.03 min; MS [ESIpos]: m/z=615 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.01 (s, 3H), 3.36 (dd, 1H), 3.68 (dd, 1H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.31 (m, 1H), 4.44-4.53 (m[AB], 2H), 5.73-5.82 (m, 1H), 6.89 (d, 1H), 7.53 (t, 1H), 7.59-7.64 (m, 2H), 7.70-7.82 (m, 5H), 9.08 (d, 1H)。
Embodiment 137
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-(methyl sulphonyl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
The compound of the embodiment 8A of 416mg (1.14 mmol), the compound of the embodiment 149A of 380 mg (1.25 mmol), the EDC of 262 mg (1.37 mmol), the N of the HOBt of 184 mg (1.37mmol) and 238 μ L (1.37mmol), N '-diisopropylethylamine at room temperature stirs 1 hour in the DMF of 13.4 ml.Preparation property HPLC[method 23 for whole solution] purify.Suitable fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 458 mg (theoretical value 65%).
LC-MS [method 4] R t=1.06 min; MS [ESIpos]: m/z=615 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 26b going up mutually in chirality] separate: referring to embodiment 138 and embodiment 139.
Embodiment 138
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-(methyl sulphonyl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 647711DEST_PATH_IMAGE258
The first wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 137 of 450 mg by method 26b.The product obtaining is further purified by preparation property HPLC [method 20].The dry title compound that obtains 151 mg in HV.
Chiral analysis HPLC [method 27a]: R t=3.61 min.
LC-MS [method 5] R t=1.07 min; MS [ESIpos]: m/z=615 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.99 (s, 3H), 3.69 (d, 2H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.21-4.31 (m, 1H), 4.45-4.55 (m [AB], 2H), 5.48 (q, 1H), 6.89 (d, 1H), 7.57-7.80 (m, 8H), 8.99 (d, 1H)。
Embodiment 139
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-(methyl sulphonyl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 957469DEST_PATH_IMAGE259
The last wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 137 of 450 mg by method 26b.The product obtaining is further purified by preparation property HPLC [method 20].The dry title compound that obtains 145 mg in HV.
Chiral analysis HPLC [method 27a]: R t=4.40 min.
LC-MS [method 5] R t=1.08 min; MS [ESIpos]: m/z=615 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.99 (s, 3H), 3.64-3.74 (m, 2H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.22-4.34 (m, 1H), 4.44-4.56 (m [AB], 2H), 5.45-5.53 (m, 1H), 6.91 (d, 1H), 7.57-7.80 (m, 8H), 8.98 (d, 1H)。
Embodiment 140
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-(dimethylamino-sulfonyl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 28193DEST_PATH_IMAGE260
The compound of the embodiment 8A of 221 mg (0.60 mmol), the compound of the embodiment 150A of 221mg (0.66 mmol), the EDC of 174 mg (0.91 mmol), the N of the HOBt of 122 mg (0.91mmol) and 137 μ L (0.79mmol), N '-diisopropylethylamine at room temperature stirs 2 hours in the DMF of 5.7 ml.Preparation property HPLC[method 10 for whole solution] purify.Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 337 mg (theoretical value 87%).
LC-MS [method 2] R t=2.41 min; MS [ESIpos]: m/z=644 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 28 going up mutually in chirality] separate: referring to embodiment 141 and embodiment 142.
Embodiment 141
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-(dimethylamino-sulfonyl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 894649DEST_PATH_IMAGE261
The first wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 140 of 337 mg by method 28.Products therefrom (153 mg) is further purified by preparation property HPLC [method 20].The dry title compound that obtains 120 mg in HV.
Chiral analysis HPLC [method 18d]: R t=2.56 min.
LC-MS [method 5] R t=1.13 min; MS [ESIpos]: m/z=644 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.75 (s, 6H), 3.48-3.63 (m, 2H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.20-4.33 (m, 1H), 4.49 (s, 2H), 5.33-5.41 (m, 1H), 6.90 (d, 1 H), 7.58-7.79 (m, 8H), 8.92 (d, 1H)。
Embodiment 142
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl }-N-{2-(dimethylamino-sulfonyl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 734429DEST_PATH_IMAGE261
The last wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 140 of 337 mg by method 28.Products therefrom (160 mg) is further purified by preparation property HPLC [method 10].The dry title compound that obtains 129 mg in HV.
Chiral analysis HPLC [method 18d]: R t=2.56 min.
LC-MS [method 5] R t=1.13 min; MS [ESIpos]: m/z=644 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.76 (s, 6H), 3.48-3.63 (m, 2H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.21-4.34 (m, 1H), 4.42-4.55 (m [AB], 2H), 5.34-5.44 (m, 1H), 6.92 (d, 1H), 7.58-7.79 (m, 8H), 8.91 (d, 1H)。
Embodiment 143
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(1E)-3; 3; 3-trifluoropropyl-1-alkene-1-yl]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[2-(trifluoromethyl) phenyl] ethyl ester (enantiomer-pure)
Figure 277406DEST_PATH_IMAGE262
The solution that the DMAP of the compound of the embodiment 51 of 135 mg (0.23 mmol) and 33 mg (0.27 mmol) forms in the pyridine of 1.6 ml mixes by the fluoroform acid anhydrides that drips 95 μ L (0.57 mmol), and gained mixture at room temperature stirs 3 days.Add subsequently the 1N hydrochloric acid of 2 ml, on rotatory evaporator, remove volatile constituent.Residue is dissolved in a small amount of DMSO, then by preparation property HPLC[method 10] purify.Containing fraction desolvation on rotatory evaporator of product, residue is dry in HV.This obtains the title compound of 118 mg (theoretical value 90%).
LC-MS [method 4] R t=1.13 min; MS [ESIpos]: m/z=578 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.98 (dd, 1H), 4.14 (dd, 1H), 4.48-4.58 (m [AB], 2H), 5.36-5.45 (m, 1H), 6.40-6.77 (br. s., 2H), 6.84 (dq, 1H), 7.17 (dq, 1H), 7.52 (t, 1H), 7.61-7.76 (m, 7H), 8.98 (d, 1H)。
Embodiment 144
2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3; 3,3-trifluoro propyl)-4,5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-[2-(trifluoromethyl) phenyl] urethanum (enantiomer-pure)
The soln using of the compound of the embodiment 143 of 118 mg (0.20 mmol) in the methyl alcohol of 20 ml is equipped with the Continuous Flow hydrogenation apparatus (H-Cube of 5% Pt/C catalyzer box, Thales Nano, Budapest, HC-2-SS type), under the flow velocity of the temperature of 45 DEG C and 1 ml/min, under standard pressure, be hydrogenated.On rotatory evaporator, remove methyl alcohol, preparation property HPLC purification [method 10] for residue.This obtains the title compound of 31 mg (theoretical value 26%).
LC-MS [method 2] R t=2.30 min; MS [ESIpos]: m/z=580 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.51-2.69 (m, 2H), 3.93-4.01 (m, 3H), 4.12 (dd, 1H), 4.48 (s, 2H), 5.34-5.42 (m, 1H), 6.40-6.78 (br. s., 2H), 7.49-7.55 (m, 1H), 7.60-7.76 (m, 7H), 8.94 (d, 1H)。
Embodiment 145
Ethyl carbamic acid 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[2-(trifluoromethyl) phenyl] ethyl ester (diastereisomericallypure pure)
Figure 237064DEST_PATH_IMAGE264
The compound of the embodiment 8A of 298 mg (0.81 mmol), the HOBt of the EDC of 187 mg (0.98 mmol) and 132 mg (0.98 mmol) stirs 10 minutes in the DMF of 5 ml.Gained solution is added dropwise to the compound of embodiment 187A and the N of 156 μ L (0.90 mmol) of 280 mg (0.90 mmol), in the solution that N '-diisopropylethylamine forms in the acetonitrile of 10 ml.Whole mixture at room temperature stirs 20 minutes, then, with the 1N mixed in hydrochloric acid of 3 ml, is then purified by preparative chromatography [method 10].Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 420 mg (theoretical value 83%).
LC-MS [method 4] R t=1.11 min; MS [ESIpos]: m/z=624 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 0.98 (t, 3H), 2.90-3.04 (m, 2H), 3.82 (dd, 1H), 3.92-4.03 (m, 2H), 4.11-4.20 (m, 1H), 4.20-4.32 (m, 1H), 4.49 (s, 2H), 5.35-5.44 (m, 1H), 6.88 (d, 1H), 7.20 (t, 1H), 7.53 (t, 1H), 7.58-7.65 (m, 2H), 7.68-7.79 (m, 5H), 8.96 (d, 1H)。
Embodiment 146
Ethyl carbamic acid 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(1E)-3; 3; 3-trifluoropropyl-1-alkene-1-yl]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[2-(trifluoromethyl) phenyl] ethyl ester (enantiomer-pure)
Figure 993668DEST_PATH_IMAGE265
The solution that the DMAP of the compound of the embodiment 145 of 230 mg (0.37 mmol) and 54mg (0.44 mmol) forms in the pyridine of 5 ml mixes by the fluoroform acid anhydrides that drips 155 μ L (0.92 mmol), and gained mixture at room temperature stirs a night.Add subsequently the 1N hydrochloric acid of 2 ml, on rotatory evaporator, remove volatile constituent.Residue is dissolved in a small amount of DMSO, then by preparation property HPLC[method 10] purify.Containing fraction desolvation on rotatory evaporator of product, residue is dry in HV.This obtains the title compound of 168 mg (theoretical value 75%).
LC-MS [method 4] R t=1.22 min; MS [ESIpos]: m/z=606 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 0.98 (t, 3H), 2.92-3.04 (m, 2H), 3.99 (dd, 1H), 4.13-4.20 (m, 1H), 4.48-4.59 (m[AB], 2H), 5.37-5.45 (m, 1H), 6.85 (dq, 1H), 7.17 (dq, 1H), 7.23 (t, 1H), 7.50-7.56 (m, 1H), 7.60-7.77 (m, 7H), 8.99 (d, 1H)。
Embodiment 147
Ethyl carbamic acid 2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3; 3; 3-trifluoro propyl)-4; 5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-[2-(trifluoromethyl) phenyl] ethyl ester (enantiomer-pure)
Figure 645229DEST_PATH_IMAGE266
The soln using of the compound of the embodiment 146 of 168 mg (0.28 mmol) in the methyl alcohol of 30 ml is equipped with the Continuous Flow hydrogenation apparatus (H-Cube of 5% Pt/C catalyzer box, Thales Nano, Budapest, HC-2-SS type), under the flow velocity of the temperature of 70 DEG C and 1 ml/min, under standard pressure, be hydrogenated.On rotatory evaporator, remove methyl alcohol, preparation property HPLC purification [method 20] for residue.This obtains the title compound of 96 mg (theoretical value 55%).
LC-MS [method 5] R t=1.16 min; MS [ESIpos]: m/z=608 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 0.98 (t, 3 H), 2.55-2.65 (m, 2H), 2.91-3.03 (m, 2H), 3.94-4.02 (m, 3H), 4.10-4.19 (m, 1H), 4.47 (s, 2H), 5.35-5.43 (m, 1H), 7.21 (t, 1H), 7.52 (t, 1H), 7.59-7.68 (m, 4H), 7.68-7.76 (m, 3H), 8.94 (d, 1H)。
Embodiment 148
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(2-oxo-1,3-
Figure 503595DEST_PATH_IMAGE064
azoles alkane-3-yl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 898804DEST_PATH_IMAGE267
The compound of the embodiment 8A of 187 mg (0.51 mmol), the HOBt of the EDC of 118 mg (0.61 mmol) and 87 mg (0.61 mmol) stirs 5 minutes in the DMF of 5 ml.Gained solution is added dropwise to the compound of embodiment 140A and the N of 89 μ L (0.51 mmol) of 175 mg (0.56 mmol), in the solution that N '-diisopropylethylamine forms in the DMF of 5 ml.Whole mixture at room temperature stirs 2 hours, then with the 1N mixed in hydrochloric acid of 100 ml.Extract by the ethyl acetate of 500 ml.Organic phase washes with water four times and washs once with saturated sodium-chloride water solution, then removes volatile component by dried over sodium sulfate with on rotatory evaporator.Residue is purified by preparative chromatography [method 10].Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 265 mg (theoretical value 83%), is non-enantiomer mixture (according to the about 3:1 of the ratio of NMR, according to chirality HPLC[method 27a] ratio 77:23).
LC-MS [method 4] Rt=1.09 min; MS [ESIpos]: m/z=622 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 26c going up mutually in chirality] separate: referring to embodiment 149 and embodiment 150.
Embodiment 149
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(2-oxo-1,3-
Figure 447597DEST_PATH_IMAGE064
azoles alkane-3-yl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 597956DEST_PATH_IMAGE267
The first wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 148 of 265 mg by method 26c.Products therefrom (192 mg) is further purified by preparation property HPLC [method 20].The dry title compound that obtains 126 mg in HV.
Chiral analysis HPLC [method 27a]: R t=3.75 min
LC-MS [method 4]: R t=1.09 min; MS [ESIpos]: m/z=622 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): d = 3.42-3.52 (m, 3H), 3.57 (q, 1H), 3.83 (dd, 1H), 3.97 (dd, 1H), 4.16 (t, 2H), 4.21-4.35 (m, 1H), 4.51 (s, 2H), 5.24 (q, 1H), 6.89 (d, 1H), 7.57-7.64 (m, 3H), 7.64-7.69 (m, 1H), 7.69-7.78 (m, 3H), 7.80 (s, 1H), 8.81 (d, 1H)。
Embodiment 150
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(2-oxo-1,3-
Figure 864989DEST_PATH_IMAGE064
azoles alkane-3-yl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 876938DEST_PATH_IMAGE268
The last wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 148 of 265 mg by method 26c.This obtains the title compound of 65 mg, about 90% purity.
Chiral analysis HPLC [method 27a]: R t=6.01 min
LC-MS [method 4] R t=1.08 min; MS [ESIpos]: m/z=622 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 3.43-3.53 (m, 3H), 3.57 (q, 1H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.17 (t, 2H), 4.22-4.33 (m, 1H), 4.43-4.58 (m, 2H), 5.24 (q, 1H), 6.90 (d, 1H), 7.57-7.69 (m, 4H), 7.69-7.78 (m, 3H), 7.80 (s, 1H), 8.80 (d, 1H)。
Embodiment 151
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(2-oxo-imidazole alkane-1-yl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 342555DEST_PATH_IMAGE269
The compound of the embodiment 8A of 182 mg (0.50 mmol), the HOBt of the EDC of 115 mg (0.60 mmol) and 85 mg (0.60 mmol) stirs 5 minutes in the DMF of 5 ml.Gained solution is added dropwise to the compound of embodiment 141A and the N of 87 μ L (0.50 mmol) of 170 mg (0.55 mmol), in the solution that N '-diisopropylethylamine forms in the DMF of 5 ml.Whole mixture at room temperature stirs 2 hours, then with the 1N mixed in hydrochloric acid of 100 ml.Extract by the ethyl acetate of 500 ml.Organic phase washes with water four times and washs once with saturated sodium-chloride water solution, then removes volatile component by dried over sodium sulfate with on rotatory evaporator.Residue is purified by preparative chromatography [method 10].Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 168 mg (theoretical value 54%), is non-enantiomer mixture (according to chirality HPLC[method 27a] ratio 72:25).
LC-MS [method 4] R t=1.08 min; MS [ESIpos]: m/z=621 (M+H) +
Main diastereomer is by the preparation HPLC[method 26c going up mutually in chirality] come to separate (referring to embodiment 152) with respective pure form.Less important diastereomer (diastereomer 2) (Rt[method 27a]=4.66 minutes) do not separate.
Embodiment 152
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(2-oxo-imidazole alkane-1-yl)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
Figure 601498DEST_PATH_IMAGE269
The first wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 151 of 168 mg by method 26a.The dry title compound that obtains 107 mg in HV.
Chiral analysis HPLC [method 27a]: R t=3.87 min.
LC-MS [method 4] R t=1.08 min; MS [ESIpos]: m/z=621 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.07-3.19 (m, 2H), 3.20-3.43 (m, 4H), 3.82 (dd, 1H), 3.97 (m, 1H), 4.25-4.36 (m, 1H), 4.49 (s, 2H), 5.08-5.15 (m, 1H), 6.37 (s, 1H), 6.90 (d, 1H), 7.56-7.70 (m, 5H), 7.72-7.78 (m, 3H), 8.70 (d, 1H)。
Embodiment 153
N-[1-(2-chloro-phenyl-)-2-(methylthio group) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (non-enantiomer mixture)
Figure 168876DEST_PATH_IMAGE270
The compound of the embodiment 8A of 53mg (0.14 mmol), the compound of the embodiment 147A of 38 mg (0.16 mmol), the EDC of 33 mg (0.17 mmol), the N of the HOBt of 24 mg (0.17mmol) and 30 μ L (0.17mmol), N '-diisopropylethylamine at room temperature stirs 1 hour in the DMF of 1.7 ml.Then solution use the in addition acidifying of 1N hydrochloric acid, and whole solution is with preparation property HPLC purify [method 20].Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound (theoretical value 87%) of 70 mg.
LC-MS [method 5] R t=1.16 min; MS [ESIpos]: m/z=549 (M+H) +
1h NMR (400 MHz, DMSO-d 6): δ=2.09 (2s, every kind of diastereomer of 1s/, 3H), 2.71-2.85 (m, 2H), 3.83 (dd, 1H), 3.96 (br d, 1H), 4.20-4.33 (m, 1H), 4.47-4.58 (m, 2H), 5.35-5.44 (m, 1H), 6.87-6.92 (m, be interpreted as every kind of diastereomer of 1d/, (6.89+6.90), 1H), 7.27-7.40 (m, 2H), 7.43 (br d, 1H), 7.52 (br d, 1H), 7.63 (2d, 2H), 7.74 (d, 2H), 8.82 (d, 1H).
Embodiment 154
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(methylthio group)-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 968205DEST_PATH_IMAGE271
The compound of the embodiment 8A of 303mg (0.83 mmol), the compound of the embodiment 142A of 248 mg (0.91 mmol), the EDC of 191 mg (1.00 mmol), the N of the HOBt of 135 mg (1.00mmol) and 173 μ L (1.00mmol), N '-diisopropylethylamine at room temperature stirs 1 hour in the DMF of 9.8 ml.Preparation property HPLC[method 20 for whole solution] purify.Suitable fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 362 mg (theoretical value 73%).
LC-MS [method 3] R t=1.33 min; MS [ESIpos]: m/z=583 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 29 going up mutually in chirality] separate: referring to embodiment 155 and embodiment 156.
Embodiment 155
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(methylthio group)-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer I)
The first wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 154 of 360 mg by method 29.Products therefrom (148 mg) is further purified by preparation property HPLC [method 20].The dry title compound that obtains 119 mg in HV.
Chiral analysis HPLC [method 30]: R t=4.40 min.
LC-MS [method 31] R t=2.53 min; MS [ESIpos]: m/z=583 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 2.06 (s, 3H), 2.74-2.83 (m, 2H), 3.82 (dd, 1H), 3.95 (dd, 1H), 4.20-4.34 (m, 1H), 4.44-4.55 (m [AB], 2H), 5.32-5.41 (m, 1H), 6.92 (d, 1H), 7.50 (t, 1H), 7.60-7.65 (m, 2H), 7.67-7.78 (m, 5H), 8.86 (d, 1H)。
Embodiment 156
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(methylthio group)-1-[2-(trifluoromethyl) phenyl] ethyl } ethanamide (diastereomer II)
Figure 561633DEST_PATH_IMAGE271
The last wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 154 of 360 mg by method 29.Products therefrom (157 mg) is further purified by preparation property HPLC [method 20].The dry title compound that obtains 108 mg in HV.
Chiral analysis HPLC [method 30]: R t=5.97 min.
LC-MS [method 31] Rt=2.54 min; MS [ESIpos]: m/z=583 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 2.06 (s, 3H), 2.73-2.84 (m, 2H), 3.82 (dd, 1H), 3.96 (dd, 1H), 4.20-4.32 (m, 1H), 4.43-4.56 (m [AB], 2H), 5.36 (q, 1H), 6.90 (d, 1H), 7.51 (t, 1H), 7.59-7.65 (m, 2H), 7.68-7.78 (m, 5H), 8.87 (d, 1H)。
Embodiment 157
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{1-[3-(difluoromethyl) phenyl]-2-hydroxyethyl } ethanamide (non-enantiomer mixture)
The compound of the embodiment 8A of 53mg (0.14 mmol), the compound of the embodiment 155A of 39 mg (0.17 mmol), the EDC of 33 mg (0.17 mmol), the N of the HOBt of 24 mg (0.17mmol) and 30 μ L (0.17mmol), N '-diisopropylethylamine at room temperature stirs 1 hour in the DMF of 1.7 ml.Due to the partial esterification of product and reactant 8A, add the 1N lithium hydroxide aqueous solution of 0.5 ml, mixture stirs 1 hour.It uses the in addition acidifying of 1N hydrochloric acid subsequently, and whole solution is with preparation property HPLC purify [method 20].Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 362 mg (theoretical value 73%).
LC-MS [method 5] R t=1.01 min; MS [ESIpos]: m/z=535 (M+H) +
1h NMR (400 MHz, DMSO-d 6): δ=3.61 (t, 2H), 3.83 (dd, 1H), 3.96 (dd, 1H), 4.21-4.33 (m, 1H), 4.47-4.59 (m, 2H), 4.86-4.95 (m, 1H), 4.98 (t, 1H), 6.89 (t, 1H is interpreted as every kind of diastereomer of 1d/), 7.00 (dt, J=3 Hz, 56 Hz, 1H), 7.42-7.55 (m, 4H), 7.59-7.66 (m, 2H), 7.74 (dd, 2H, be interpreted as every kind of diastereomer of 1d/), 8.66 (dd, 1H, be interpreted as every kind of diastereomer of 1d/).
Embodiment 158
Thionamic acid 3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-3-[3-(trifluoromethyl) phenyl] propyl diester (non-enantiomer mixture)
Figure 953748DEST_PATH_IMAGE273
The solution that the compound of the embodiment 66 of 27 mg (48 μ mol) forms in the dry DMF of 0.5 ml and the triethylamine of 100 μ L carries out blending by the solution that drips the sulfamic acid chloride of 83 mg and form in the DMF of 2 ml.When reaction detection only shows when 20% transformation efficiency, add the sulfamic acid chloride of the solid form of other 200 mg.After 10 minutes, add the 1N hydrochloric acid of 2 ml, preparation property HPLC purification [method 10] for whole reaction mixture.Product fraction is removed volatile constituent on rotatory evaporator, and residue is dry in HV.This obtains the title compound of 12mg (theoretical value 36%), about 92% purity.
LC-MS [method 3] R t=1.25 and 1.26 min; MS [ESIpos]: m/z=646 (M+H) +
1h NMR (400 MHz, DMSO-d 6): δ=2.12 (q, 2H), 3.82 (dd, 1H), 3.92-4.04 (m, 2H), 4.04-4.13 (m, 1H), 4.22-4.32 (m, 1H), 4.44-4.59 (m, 2H), 4.98-5.07 (m, 1H), 6.91 (t, 1H is interpreted as every kind of diastereomer of 1d/), 7.48 (s, 2H), 7.56-7.78 (m, 9H), 8.84 (dd, 1H, is interpreted as every kind of diastereomer of 1d/).
Embodiment 159
Thionamic acid 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-2-[3-(trifluoromethyl) phenyl] ethyl ester (non-enantiomer mixture)
Figure 659536DEST_PATH_IMAGE274
The compound of the embodiment 8A of 187 mg (0.51 mmol), 200 mg (about 90% purity, 0.56 mmol) the compound of embodiment 157A, the EDC of 117 mg (0.61 mmol), the N of the HOBt of 83 mg (0.61mmol) and 107 μ L (0.61 mmol), N '-diisopropylethylamine at room temperature stirs 1 hour in the DMF of 5.9 ml.This solution is used the in addition acidifying of 1N hydrochloric acid subsequently, and whole solution is with preparation property HPLC purify [method 10].Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 215mg (theoretical value 60%), about 90% purity.
LC-MS [method 3] R t=1.26 and 1.27 min; MS [ESIpos]: m/z=632 (M+H) +
1h NMR (400 MHz, DMSO-d 6): δ=3.83 (dd, 1H), 3.97 (br d, 1H), 4.18-4.34 (m, 3H), 4.51-4.63 (m, 2H), 5.28-5.35 (m, 1H), 6.91 (t (being interpreted as every kind of diastereomer of 1d/, 1H), 7.53-7.83 (m, 10H), 8.95+8.97 (every kind of diastereomer of 1d/, 1H).
Embodiment 160
N-[2-(carbamido group)-1-(2,3-dichlorophenyl) ethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(1E)-3,3,3-trifluoropropyl-1-alkene-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (enantiomer-pure)
Figure 994702DEST_PATH_IMAGE275
According to the mode identical with embodiment 146, obtain title compound (22 mg, theoretical value 21%) from the compound of the embodiment 62 of 110mg (185 μ mol).
LC-MS [method 3] R t=1.28 min; MS [ESIpos]: m/z=577 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 3.19-3.38 (m, 2H), 4.45-4.60 (m, 2H), 5.14-5.23 (m, 1H), 5.54 (s, 2H), 6.14 (t, 1H), 6.85 (dq, 1H), 7.19 (dq, 1H), 7.33-7.42 (m, 2H), 7.55 (dd, 1H), 7.63-7.71 (m, 4H), 8.99 (d, 1H)。
Embodiment 161
N-{2-(carbamido group)-1-[3-(trifluoromethyl) phenyl] ethyl }-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(1E)-3,3,3-trifluoropropyl-1-alkene-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (enantiomer-pure)
Figure 536673DEST_PATH_IMAGE276
According to the mode identical with embodiment 146, obtain title compound (15 mg, theoretical value 18%) from the compound of the embodiment 57 of 87mg (146 μ mol).
LC-MS [method 4] R t=1.09 min; MS [ESIpos]: m/z=577 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ = 3.18-3.40 (m, 2H), 4.46-4.60 (m, 2H), 4.89-4.97 (m, 1H), 5.55 (s, 2H), 6.05 (t, 1H), 6.86 (dq, 1H), 7.19 (dq, 1H), 7.54-7.69 (m, 8H), 8.86 (d, 1H)。
Embodiment 162
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-(aminosulfonyl amido)-1-[3-(trifluoromethyl) phenyl] ethyl } ethanamide (non-enantiomer mixture)
Figure 615487DEST_PATH_IMAGE277
The compound of the embodiment 8A of 62.2 mg (0.17 mmol), the compound of the embodiment 134A of 53 mg (0.19 mmol), the HOBt of the EDC of 39 mg (0.20 mmol) and 20 mg (0.20 mmol) at room temperature stirs a night in the DMF of 2 ml.Add subsequently the 1N hydrochloric acid of 1 ml, preparation property HPLC purification [method 20] for whole solution.Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound (theoretical value 78%) of 84 mg.
LC-MS [method 5] R t=1.03 min; MS [ESIpos]: m/z=631 (M+H) +
1h-NMR (400 MHz, DMSO-d 6): δ=3.20 (br. t, 1H), 3.82 (dd, 1H), 3.96 (dt, be interpreted as every kind of diastereomer of 1 dd/, 1H), 4.21-4.34 (m., 1H), 4.45-4.62 (m, 2H), 5.05-5.14 (m, 1H, ) 6.61-6.65 (m, 2H), 6.70-6.78 (m, 1H), 6.91 (dd, be interpreted as every kind of diastereomer of 1d/, 2H), 7.56-7.64 (m, 5H), 7.70 (br.s, 1H), 7.74-7.78 (m, 2H), 8.62-8.70 (t, 1H, be interpreted as every kind of diastereomer of 1d/).
Embodiment 163
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-hydroxyl-1-[3-(trifluoromethyl) phenyl] ethyl }-N-methylacetamide (non-enantiomer mixture)
Figure 175782DEST_PATH_IMAGE278
The compound of the embodiment 8A of 1.87 g (5.12 mmol), the HOBt of the EDC of 1.18 mg (6.14 mmol) and 874 mg (6.14 mmol) stirs 5 minutes in the DMF of 100 ml.Gained solution is added dropwise to the compound of embodiment 156A and the N of 892 μ L (5.12 mmol) of 1.44 g (5.63 mmol), in the solution that N '-diisopropylethylamine forms in the DMF of 50 ml.Whole mixture at room temperature stirs 1 hour, then with the 1N mixed in hydrochloric acid of 100 ml.Extract by the ethyl acetate of 500 ml.Organic phase washes with water four times and washs once with saturated sodium-chloride water solution, then removes volatile component by dried over sodium sulfate with on rotatory evaporator.Residue is purified by preparative chromatography (method 20 and and then by method 32).Product fraction desolvation on rotatory evaporator, residue is dry in HV.This obtains the title compound of 637 mg (theoretical value 22%), is non-enantiomer mixture.
LC-MS [method 4] R t=1.08 min; MS [ESIpos]: m/z=567 (M+H) +
Two kinds of diastereomers are by the preparation HPLC[method 26d going up mutually in chirality] separate: referring to embodiment 164 and embodiment 165.
Embodiment 164
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-hydroxyl-1-[3-(trifluoromethyl) phenyl] ethyl }-N-methylacetamide (diastereomer I)
Figure 681849DEST_PATH_IMAGE278
The first wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 163 of 200 mg by method 26d.Products therefrom (93 mg) is further purified by preparation property HPLC [method 20].The dry title compound that obtains 80 mg in HV.
Chiral analysis HPLC [method 27b]: R t=4.82 min.
LC-MS [method 4] R t=1.08 min; MS [ESIpos]: m/z=567 (M+H) +
NMR shows two kinds of rotational isomers, A and B, and the ratio of about 2:1:
1H NMR (400 MHz, DMSO-d 6): δ = 2.64 (s, 3H B), 2.94 (s, 3H A), 3.77-4.04 (m, 4H), 4.21-4.33 (m, 1H), 4.78 (d, 1H A), 4.90 (d, 1H B), 4.91 (d, 1H A), 5.00 (d, 1H B), 5.05 (t, 1H A), 5.18-5.25 (m, 1H B), 5.28-5.33 (m, 1H B), 5.57 (t, 1H A), 6.89 (d, 1H A), 6.92 (d, 1H B), 7.55-7.72 (m, 6H), 7.76 (d, 2H)。
Embodiment 165
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-{2-hydroxyl-1-[3-(trifluoromethyl) phenyl] ethyl }-N-methylacetamide (diastereomer II)
Figure 898067DEST_PATH_IMAGE278
The last wash-out diastereomer being obtained from the diastereomer chromatographic separation of the compound of the embodiment 163 of 200 mg by method 26d.Products therefrom (96 mg) is further purified by preparation property HPLC [method 20].The dry title compound that obtains 63 mg in HV.
Chiral analysis HPLC [method 27b]: R t=6.60 min.
LC-MS [method 4] R t=2.54 min; MS [ESIpos]: m/z=567 (M+H) +
NMR is (at D 6in-DMSO) show two kinds of rotational isomers, A and B, the ratio of about 2:1:
1H NMR (400 MHz, DMSO-d 6): δ = 2.63 (s, 3H B), 2.94 (s, 3H A), 3.81-4.03 (m, 4H), 4.21-4.33 (m, 1H), 4.78 (d, 1H A), 4.91 (d, 1H A), 4.90-5.03 (m [AB], 2H B), 5.05 (t, 1H A), 5.21 (t, 1H B), 5.31 (t, 1H B), 5.57 (t, 1H A), 6.89 (d, 1H b), 6.91 (d, 1H A), 7.55-7.73 (m, 6H), 7.758 (d, 2H B), 7.764 (d, 2H A)。
Embodiment 166
N-[1-(the chloro-2-fluorophenyl of 3-)-2-hydroxyethyl]-2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl } ethanamide (non-enantiomer mixture)
The compound of the embodiment 8A of 150 mg (0.39 mmol) is dissolved in the DMF of 1 ml, mix with the EDC of 87 mg (0.51 mmol) with the HOBt of 68 mg (0.51 mmol), then at room temperature stir 20 minutes.The compound of embodiment 161A and the triethylamine of 60 μ L (0.43 mmol) that add subsequently 115 mg (0.43 mmol), mixture at room temperature stirs 16 hours.For aftertreatment, add the 1N hydrochloric acid of 100 μ L, crude product is directly by preparation property HPLC[method 19] purify.This obtains the target compound of 171 mg (theoretical value 82%), is non-enantiomer mixture.
LC-MS [method 3] R t=1.18 and 1.19 min; MS [ESIpos]: m/z=537 (M+H) +
1h-NMR (400 MHz, CDCl 3): δ=3.24 and 3.48 (2m, 1H), 3.58-3.68 (m, 1H), 3.73-3.81 (2m, 1H), 3.83-4.16 (m, 3H), 4.47-4.77 (m, 3H), 5.28 and 5.62 (2d, 1H), 5.27-5.37 (m, 1H), 6.98 and 7.56 (2d, 1H), 7.01-7.10 (m, 1H), 7.12-7.22 (m, 1H), 7.29-7.37 (m, 1H), 7.46 and 7.49 (2d, 2H), 7.62 and 7.68 (2d, 2H).(part of the signal of dual group of non-enantiomer mixture splits).
Obtain similarly following compounds:
Figure 950971DEST_PATH_IMAGE281
Figure 199025DEST_PATH_IMAGE282
Figure 154529DEST_PATH_IMAGE284
Figure 815448DEST_PATH_IMAGE285
Figure 740679DEST_PATH_IMAGE286
Embodiment 187
2-{3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3, the fluoro-2-hydroxypropyl of 3,3-tri-]-4,5-dihydro-1H-1,2,4-triazol-1-yl }-N-[3-hydroxyl-1-(2-p-methoxy-phenyl) propyl group] ethanamide (non-enantiomer mixture)
Figure 27304DEST_PATH_IMAGE287
The compound of the embodiment 8A of 134 mg (0.37 mmol) is dissolved in the DMF of 1 ml, mix with the EDC of 106 mg (0.55 mmol) with the HOBt of 74 mg (0.55 mmol), then at room temperature stir 20 minutes.The compound of embodiment 172A and the DIPEA of 85 μ L (0.51 mmol) that add subsequently 88 mg (0.40 mmol), mixture at room temperature stirs 16 hours.For aftertreatment, add the 1N hydrochloric acid of 100 μ L, crude product is directly by preparation property HPLC[method 19] purify.This obtains the target compound of 77 mg (theoretical value 40%), is non-enantiomer mixture.
LC-MS [method 4] R t=0.99 min; MS [ESIpos]: m/z=529 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 1.70-1.87 (m, 2 H), 3.35-3.45 (m, 2 H), 3.78 (s, 3 H), 3.80-3.86 (m, 1 H), 3.92-4.01 (m, 1 H), 4.22-4.33 (m, 1 H), 4.40-4.56 (m, 3 H), 5.16-5.26 (m, 1 H), 6.86-6.99 (m, 3 H), 7.16-7.31 (m, 2 H), 7.59-7.68 (m, 2 H), 7.71-7.79 (m, 2 H), 8.42 (d, 1 H)。(part of the signal of dual group of non-enantiomer mixture splits).
Embodiment 188
Carboxylamine 3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-3-(2-p-methoxy-phenyl) propyl diester (non-enantiomer mixture)
Figure 354380DEST_PATH_IMAGE288
The compound of the embodiment 8A of 237 mg (0.65 mmol) is dissolved in the DMF of 2 ml, mix with the EDC of 174 mg (0.91 mmol) with the HOBt of 123 mg (0.91 mmol), then at room temperature stir 20 minutes.Then the compound of embodiment 174A and the DIPEA of 129 μ L (0.78 mmol) that add 186 mg (0.71 mmol), mixture at room temperature stirs 16 hours.For aftertreatment, add the 1N hydrochloric acid of 100 μ L, crude product is directly by preparation property HPLC[method 19] purify.This obtains the target compound of 123 mg (theoretical value 33%), is non-enantiomer mixture.
LC-MS [method 5] R t=1.01 min; MS [ESIpos]: m/z=572 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 1.71-1.99 (m, 2 H), 3.78 (s, 3 H), 3.80-4.00 (m, 4 H), 4.22-4.34 (m, 1 H), 4.40-4.60 (m, 2 H), 5.14-5.31 (m, 1 H), 6.46 (br. s., 2 H), 6.85-7.01 (m, 3 H), 7.16-7.33 (m, 2 H), 7.59-7.67 (m, 2 H), 7.69-7.80 (m, 2 H), 8.38-8.54 (m, 1 H)。(part of the signal of dual group of non-enantiomer mixture splits).
Non-enantiomer mixture is by the preparation HPLC[method 13a going up mutually in chirality] separate: referring to embodiment 189 and 190.
Embodiment 189
Carboxylamine 3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-3-(2-p-methoxy-phenyl) propyl diester (diastereomer I)
Figure 451780DEST_PATH_IMAGE289
The first wash-out diastereomer obtaining from the separation of embodiment 188.
Output: 33 mg (theoretical value 9%).
Chiral analysis HPLC [method 9]: R t=3.46 min
LC-MS [method 5] R t=1.01 min; MS [ESIpos]: m/z=572 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 1.81-2.00 (m, 2 H), 3.79 (s, 3 H), 3.81-4.07 (m, 4 H), 4.22-4.35 (m, 1 H), 4.44-4.56 (m, 2 H), 5.17-5.29 (m, 1 H), 6.47 (br. s., 2 H), 6.87-7.01 (m, 3 H), 7.19-7.33 (m, 2 H), 7.63 (d, 2 H), 7.76 (d, 2 H), 8.50 (d, 1 H)。
Embodiment 190
3-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2,4-triazol-1-yl } ethanoyl) amino]-3-(2-p-methoxy-phenyl) propyl carbamate (diastereomer II)
Figure 864307DEST_PATH_IMAGE289
The last wash-out diastereomer obtaining from the separation of embodiment 188.
LC-MS [method 5] R t=1.00 min; MS [ESIpos]: m/z=572 (M+H) +
Chiral analysis HPLC [method 9]: R t=3.83 min
Output: 47 mg (theoretical value 12%).
1H NMR (400 MHz, DMSO-d 6): δ = 1.81-1.98 (m, 2 H), 3.78 (s, 3 H), 3.81-4.00 (m, 4 H), 4.21-4.34 (m, 1 H), 4.42-4.58 (m, 2 H), 5.17-5.26 (m, 1 H), 6.44 (br. s., 2 H), 6.87-7.00 (m, 3 H), 7.20-7.30 (m, 2 H), 7.62 (d, 2 H), 7.76 (d, 2 H), 8.48 (d, 1 H)。
Embodiment 191
Carboxylamine 2-({ [3-(4-chloro-phenyl-)-4-(2-luorobenzyl)-5-oxo-4; 5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-[2-(trifluoromethyl) phenyl] ethyl ester (enantiomer II)
Figure 689043DEST_PATH_IMAGE290
By [3-(4-chloro-phenyl-)-4-(2-luorobenzyl)-5-oxo-4 of consumption 30 mg (0.08 mmol), 5-dihydro-1H-1,2,4-triazol-1-yl] acetic acid is (according to WO2007/134862, embodiment 154A preparation) be dissolved in the DMF of 1 ml, then this solution mixes with the EDC of 21 mg (0.11 mmol) with the HOBt of 15 mg (0.11 mmol), at room temperature stirs subsequently 20 minutes.The compound that adds subsequently the embodiment 180A of 23 mg (0.09 mmol), mixture at room temperature stirs 16 hours.For aftertreatment, add the 1N hydrochloric acid of 50 μ L, crude product is directly by preparation property HPLC[method 19] purify.This obtains the target compound of 34 mg (theoretical value 69%).
LC-MS [method 4] R t=1.09 min; MS [ESIpos]: m/z=592 (M+H)+
1H NMR (400 MHz, DMSO-d6): δ = 3.98 (dd, 1H), 4.13 (dd, 1H), 4.47-4.57 (m, 2H), 5.01 (s, 2H), 5.37-5.44 (m, 1H), 6.59 (br. s., 2H), 7.02-7.17 (m, 3H), 7.26-7.34 (m, 1H), 7.48-7.55 (m, 5H), 7.68-7.77 (m, 3H), 8.98 (d, 1H)。
Obtain similarly following compounds:
Figure 870626DEST_PATH_IMAGE291
Figure 483157DEST_PATH_IMAGE294
Embodiment 202
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl } ethanoyl) amino]-2-(2,3-dichlorophenyl) ethyl ester (diastereomer I)
Figure 581563DEST_PATH_IMAGE295
The first wash-out diastereomer being obtained from the separation of the non-enantiomer mixture of embodiment 199 by method 11b.
Output: 43 mg (theoretical value 32%).
Chiral analysis HPLC [method 12a]: R t=4.50 min
LC-MS [method 4] R t=1.05 min; MS [ESIpos]: m/z=596 and 598 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.82 (dd, 1H), 3.95 (dd, 1H), 4.02-4.15 (m, 2H), 4.22-4.33 (m, 1H), 4.46-4.58 (m, 2H), 5.41-5.48 (m, 1H), 6.60 (s br., 2H), 6.91 (d, 1H), 7.39 (t, 1H), 7.45-7.50 (m, 1H), 7.56-7.66 (m, 3H), 7.74 (d, 2H), 8.99 (d, 1H)。
Embodiment 203
Carboxylamine 2-[({3-(4-chloro-phenyl-)-5-oxo-4-[(2S)-3; 3; the fluoro-2-hydroxypropyl of 3-tri-]-4; 5-dihydro-1H-1; 2; 4-triazol-1-yl } ethanoyl) amino]-2-(2,3-dichlorophenyl) ethyl ester (diastereomer II)
Figure 207716DEST_PATH_IMAGE295
The last wash-out diastereomer being obtained from the separation of the non-enantiomer mixture of embodiment 199 by method 11b.
Output: 50 mg (theoretical value 41%).
Chiral analysis HPLC [method 12a]: R t=6.55 min
LC-MS [method 4] R t=1.05 min; MS [ESIpos]: m/z=596 and 598 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.82 (dd, 1H), 3.96 (dd, 1H), 4.02-4.16 (m, 2H), 4.22-4.29 (m, 1H), 4.47-4.57 (m, 2H), 5.40-5.48 (m, 1H), 6.60 (s br., 2H), 6.89 (d, 1H), 7.40 (t, 1H), 7.46-7.50 (m, 1H), 7.57-7.65 (m, 3H), 7.74 (d, 0H), 9.00 (d, 1H)。
Embodiment 204
Carboxylamine 2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4; 5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-(2,3-dichlorophenyl) ethyl ester (enantiomer I)
Figure 407884DEST_PATH_IMAGE296
The first wash-out enantiomer being obtained from the separation of the enantiomeric mixture of embodiment 201 by method 25.
Output: 128 mg (theoretical value 36%).
Chiral analysis HPLC [method 27d]: R t=4.35 min
LC-MS [method 3] R t=1.24 min; MS [ESIpos]: m/z=580 and 582 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.52-2.68 (m, 2H), 3.97 (t, 2H), 4.02-4.15 (m, 2H), 4.46-4.55 (m, 2H), 5.40-5.47 (m, 1H), 6.40-6.80 (m br., 2H), 7.38 (t, 1H), 7.47 (dd, 1H), 7.56-7.68 (m, 5H), 8.97 (d, 1H)。
Embodiment 205
Carboxylamine 2-({ [3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4; 5-dihydro-1H-1; 2,4-triazol-1-yl] ethanoyl } amino)-2-(2,3-dichlorophenyl) ethyl ester (enantiomer II)
The last wash-out enantiomer being obtained from the separation of the enantiomeric mixture of embodiment 201 by method 25.
Output: 135 mg (theoretical value 40%).
Chiral analysis HPLC [method 27d]: R t=5.04 min
LC-MS [method 3] R t=1.24 min; MS [ESIpos]: m/z=580 and 582 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 2.52-2.68 (m, 2H), 3.97 (t, 2H), 4.02-4.15 (m, 2H), 4.46-4.55 (m, 2H), 5.40-5.47 (m, 1H), 6.40-6.80 (m br., 2H), 7.38 (t, 1H), 7.47 (dd, 1H), 7.56-7.68 (m, 5H), 8.97 (d, 1H)。
Embodiment 206
Carboxylamine 2-({ [4-(4-chloro-phenyl-)-2-oxo-3-(3; 3; the fluoro-2-hydroxypropyl of 3-tri-)-2,3-dihydro-1H-imidazoles-1-yl] ethanoyl } amino)-2-[3-(trifluoromethyl) phenyl] ethyl ester (non-enantiomer mixture)
Figure 730598DEST_PATH_IMAGE297
By [4-(4-chloro-phenyl-)-2-oxo-3-(3 of the embodiment 184A of consumption 58 mg (0.11 mmol), 3, the fluoro-2-hydroxypropyl of 3-tri-)-2,3-dihydro-1H-imidazoles-1-yl] acetic acid is dissolved in the DMF of 2 ml, gained solution mixes with the EDC of 28 mg (0.15 mmol) with the HOBt of 20 mg (0.15 mmol), at room temperature stirs subsequently 20 minutes.The compound that adds subsequently the embodiment 183A of 42 mg (0.12 mmol), mixture at room temperature stirs 16 hours.For aftertreatment, add the 1N hydrochloric acid of 100 μ L, crude product is directly by preparation property HPLC[method 19] purify.This obtains the target compound of 13 mg (theoretical value 18%).
LC-MS [method 3] R t=1.23 min; MS [ESIpos]: m/z=595 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.74 (dd, 1H), 3.87 (dd, 1H), 4.05-4.15 (m, 2H), 4.19-4.28 (m, 1H), 4.32-4.39 (m, 2H), 5.12-5.21 (m, 1H), 6.59 (s br., 2H), 6.68-6.74 (m, 2H), 7.47-7.77 (m, 8H), 8.87 (d, 1H)。
Embodiment 207
Carboxylamine 2-({ [4-(4-chloro-phenyl-)-2-oxo-3-(3; 3; the fluoro-2-hydroxypropyl of 3-tri-)-2,3-dihydro-1H-imidazoles-1-yl] ethanoyl } amino)-2-[2-(trifluoromethyl) phenyl] ethyl ester (non-enantiomer mixture)
Figure 340702DEST_PATH_IMAGE298
According to the mode same with the Compound Phase of embodiment 206, [4-(4-chloro-phenyl-)-2-oxo-3-(3 of the embodiment 185A of 58 mg (0.11 mmol), 3, the fluoro-2-hydroxypropyl of 3-tri-)-2,3-dihydro-1H-imidazoles-1-yl] acetic acid reacts with the compound of the embodiment 180A of 42 mg (0.12 mmol).This obtains the target compound of 12 mg (theoretical value 18%).
LC-MS [method 5] R t=1.06 min; MS [ESIpos]: m/z=595 (M+H) +
1H NMR (400 MHz, DMSO-d 6): δ = 3.73 (dd, 1H), 3.86 (dd, 1H), 3.98 (dd, 1H), 4.13 (dd, 1H), 4.19-4.27 (m, 1H), 4.27-4.38 (m, 2H), 5.37-5.45 (m, 1H), 6.59 (s br., 2H), 6.68-6.74 (m, 2H), 7.47-7.56 (m, 6H), 7.69-7.77 (m, 4H), 8.95 (d, 1H)。
B. the evaluation of pharmacological activity
abbreviation:
EDTA ethylenediamine tetraacetic acid (EDTA)
The improved Eagle substratum of DMEM Dulbecco
FCS foetal calf serum
HEPES 4-(2-hydroxyethyl)-1-piperazine ethane sulfonic acid
SmGM smooth muscle cell growth substratum
Tris-HCl 2-amino-2-(methylol)-1,3-PD hydrochloride
UtSMC Uterine Smooth Cell.
The pharmacological action of the compounds of this invention can disclose in following analysis:
B-1. measure the in vitro cell analysis of antidiuretic hormone receptor active
The active quantitative analysis of the agonist of the V1a of people and rat and V2 antidiuretic hormone acceptor and the qualification of antagonist and material described here is undertaken by recombinant cell lines.These cells come from hamster ovarian epithelial cell (Chinese Hamster Ovary, CHO K1, ATCC:American Type Culture Collection, Manassas, VA 20108, USA) at first.Test clone is from forming the improved form of having expressed calcium sensitivity luminescent protein-aequorin; this luminescent protein-after with cofactor Coelenterazin restructuring-in the time that free calcium concentration improves can luminous (Rizzuto R.; Simpson A.W.; Brini M., Pozzan T.; Nature 358 (1992) 325-327).In addition, the ground transfection of this cytotostatic V1a or the V2 acceptor of people or rat.For Gs-coupling V2 acceptor, this other gene of cytotostatic ground transfection, it is the G mixing α 16protein coding (Amatruda T.T., Steele D.A., Slepak V.Z., Simon M.I., Proc. Nat. Acad. Sci. USA 88 (1991), 5587-5591), independently or as fusion gene.Gained antidiuretic hormone acceptor test cell is discharged caused hormesis for recombinant expressed antidiuretic hormone acceptor and is reacted in the cell of calcium ion, this can carry out quantitative analysis (Milligan G. by aequorin luminous intensity by the photometer with suitable, Marshall F., Rees S., Trends in Pharmaco. Sci. 17 (1996) 235-237).
testing sequence:before test one day, cell is by developing medium (DMEM, 10% FCS o'clock in 384 hole microtiter plates, 2mM glutamine, 10mM HEPES) in, and remain on cell culture apparatus (96% humidity, 5% v/v carbonic acid gas, 37 DEG C) in.On the same day of test, this developing medium is substituted (140 mM sodium-chlor by Tyrode solution, 5 mM Repone K, 1 mM magnesium chloride, 2 mM calcium chloride, 20 mM glucose, 20 mM HEPES), the latter is contained cofactor Coelenterazin (50 μ M) in addition, and then this microtiter plate is cultivated other 3-4 hour.The substances of various concentration, through within 10-20 minute, joining in the hole of microtiter plate, is added to agonist [Arg8]-antidiuretic hormone afterwards, and the optical signal obtaining is measured immediately in photometer.Use GraphPad PRISM computer program (3.02 editions) to calculate IC50 value.
Following table listed the compounds of this invention for transfection the representative IC of clone of people V1a or V2 acceptor 50value:
Table 1:
No. embodiment IC 50 hV1a [μM] IC 50 hV2 [μM]
2 0.0076 0.0026
10 0.0104 0.0063
14 0.001 0.0089
20 0.0015 0.0063
24 0.0045 0.0013
26 0.0009 0.0032
34 0.003 0.0015
39 0.0014 0.0078
44 0.044 0.0017
45 0.0055 0.0025
48 0.0052 0.0044
51 0.001 0.0085
53 0.0015 0.0049
57 0.0029 0.0022
60 0.0005 0.0045
62 0.0036 0.001
65 0.0168 0.0168
69 0.0016 0.0097
70 0.0016 0.0099
73 0.0108 0.0016
74 0.0216 0.0024
75 0.513 0.0592
78 0.0211 0.0304
87 0.0038 0.0058
89 2.88 0.29
90 0.0886 0.231
94 0.251 0.0723
95 0.0573 0.0192
96 0.0713 0.0402
112 0.0024 0.006
115 0.0035 0.0076
121 0.0009 0.0014
126 0.0018 0.0018
136 0.0039 0.024
141 0.036 0.0048
144 0.0014 0.0139
149 0.002 0.015
152 0.0022 0.0071
156 0.0019 0.01
157 0.0124 0.0051
159 0.0043 0.0018
163 0.594 0.0077
167 0.003 0.0054
168 0.087 0.076
172 0.091 0.136
182 0.304 0.028
184 0.072 0.0266
185 0.055 0.045
188 0.0082 0.0099
191 0.0023 0.0248
203 0.0027 0.0044
207 0.0033 0.101
B-2. detect antidiuretic hormone V1a receptor antagonist for fibrosis before the in vitro cell analysis of the effect that produces of the adjusting of gene
Copy quantity from clone H9C2 endogenous rat heart separate tissue, that be expressed as myocardial cell's type (American Type Culture Collection ATCC No. CRL-1446) ground with height and express antidiuretic hormone V1A acceptor AVPR1A, and AVPR2 expresses and can not detect.The cell analysis that regulates the restraining effect being produced by receptor antagonist to carry out for the AVPR1A acceptor dependency for genetic expression, program is as follows:
H9C2 cell is seeded in the 12-hole microtiter plate that cell cultures uses with the cell density of 100 000 cells/well, there is Opti-MEM medium (the Invitrogen Corp. Carlsbad CA of 1.0 ml of 2% FCS and 1% penicillin/streptomycin solution (Invitrogen Cat. No. 10378-016), USA, Cat. No. 11058-021) in, and remain on cell culture apparatus (96% humidity, 5% v/v carbonic acid gas, 37 DEG C) in.After 24 hours, in each group (triad) respectively being formed by three holes, add carrier soln (negative contrast), antidiuretic hormone solution: [Arg8]-antidiuretic hormone acetic ester (Sigma Cat. No. V9879) or substances (being dissolved in carrier: the water that has 20% (by volume) ethanol) and antidiuretic hormone solution.In cell cultures, final antidiuretic hormone concentration is 0.05 μ M.Substances solution joins in cell culture fluid with less volume, and therefore, in cell analysis, the ultimate density of 0.1% ethanol is not exceeded.After the incubation time of 6 hours, culture supernatant liquid is sucked out, adherent cell is dissolved in the RLT buffer reagent (Qiagen of 250 μ L, Ratingen, Cat. No. 79216) in, then by using RNeasy test kit (Qiagen, Cat. No. 74104) isolation of RNA from this lysate.Follow by DNAse digestion (Invitrogen Cat. No. 18068-015), cDNA synthetic (Promaga ImProm-II Reverse Transcription System Cat. No. A3800) and employing pPCR MasterMix RT-QP2X-03-075 are (from Eurogentec, Seraing, Belgium obtains) RTPCR that carries out.Whole programs is carried out according to the working regulation of test reagent manufacturers.There is the Primer3Plus program of the probe of 6-FAM-TAMRA mark by use, select the primer sets of RTPCR taking mRNA gene order (NCBI Genbank Entrez Nucleotide Data Base) as basis.For the cell that is determined at each analysis batch relatively the RTPCR program of mrna expression be according to instrumentation specification sheets, by using the Applied Biosystems ABI Prism 7700 Sequence Detector to carry out in 96-hole or 384-hole microtiter plate formats.Relative genetic expression is Δ-Δ Ct value [the Applied Biosystems being obtained by the expression level of reference ribosomal protein L-32 gene (Genbank Acc. No. NM_013226) and threshold value Ct value=35 of Ct, User Bulletin No. 2 ABI Prism 7700 SDS December 11,1997 (10/2001 upgrading)] represent.
B-3. detect the in vivo test of cardiovascular effect: for the blood pressure measurement (antidiuretic hormone " challenge " model) of anesthetized rat
In the male Sprague-Dawley rat under ketamine/xylazine/Sodital injecting anesthetic (250-350 g body weight), will pre-install the polyethylene tube (PE-50 containing the isotonic sodium chlorrde solution of heparin (500 IU/ml); Intramedic) insert in jugular vein and femoral vein, then tie up (tied in).Via a venous inlet, utilize injector to inject arginine-antidiuretic hormone; Substances is injected into via second venous inlet.For the mensuration of cystolic blood pressure, catheter pressure (Millar SPR-320 2F) is embedded to this carotid artery.Arterial cannulation is connected to pressure transmitter, and it is transferred to its signal in the logger computer that suitable logging software is housed.In typical experiment, laboratory animal was with the interval of 10-15 minute, with the pill injection of in succession carrying out for 3-4 time, use the arginine-antidiuretic hormone in isotonic sodium chlorrde solution (30 ng/kg) of specified amount, and in the time that blood pressure reaches initial level again, material to be tested is as the pill in suitable solvent, in the case of having the follow-up perfusion of carrying out, uses.After this, at specific time interval (10-15 minute), again use and the antidiuretic hormone that starts same amount.Taking pressure value as basis, offset in substances in the degree of rising blood pressure effect of antidiuretic hormone and measure.Control animal only receives solvent, instead of substances.
After intravenous administration, compound of the present invention, compared with solvent control example, causes the caused elevation of blood pressure for arginine-antidiuretic hormone to produce restraining effect.
B-4. detect the in vivo analysis of this cardiovascular effect: the diuresis research of carrying out for the sentient rat in metabolic test cage
Wei Sita (Wistar) rat (220-400 g body weight) keeps ad lib (Altromin) and drinking-water.In experimentation, the free drinking-water state of the middle maintenance of metabolic test cage (Tecniplast Deutschl and GmbH, D-82383 Hohenpei enberg) that the each leisure of animal is suitable for the rat of this weight reaches 4-8 hour.In the beginning of experiment, this animal adopts gastrogavage, and material to be tested is administered in stomach in the suitable solvent of 1-3 ml volume/kg body weight.Control animal receives only solvent.The test of controlled trial and material is parallel carrying out on the same day.Control group and material-dosage group are respectively made up of 4-8 animal.In experimentation, the urine of animal excretion is collected in the receptor of cage bottom continuously.Measure individually the volume/time per unit of urine for every animal, and in urine the concentration of the sodium of draining and potassium ion measure by the standard method of flame emission spectrometry.In order to obtain the urine of enough volumes, these animals are at the water (typically 10 ml/ pers kilogram of body weight) that starts to have given by gastrogavage specified amount of experiment.Before experiment starts and after experiment finishes, measure the body weight of each animal.
After oral, with control animal comparison, what compound of the present invention caused increasing urinates, and this mainly increases excretion (aquaresis) based on water.
B-5. detect the in vivo analysis of cardiovascular effect: for the Hemodynamics Study of anesthesia dog
Male or the female mongrel (Mongrels of body weight between 20-30 kg, Marshall BioResources, USA) with Sodital (30 mg/kg iv, Narcoren, Merial, Germany) anaesthetize to carry out surgical operation and haemodynamics and functional study end (terminii).Alcuronium chloride (Alloferin, ICN Pharmaceuticals, Germany, 3 mg/ animal iv) is in addition as muscle relaxant.These dogs are inserted into pipe and pass into oxygen/ambient air mixture (40/60%) (about 5-6 L/min).Use Draeger company (Sulla 808) ventilator to ventilate and use carbon dioxide interferometer (Engstr m) monitors.
Continous pouring by Sodital (50 μ g/kg/minute) maintains anesthesia; Fentanyl is as anodyne (10 μ g/kg/hour).It is to use isoflurane (1-2% (by volume)) that the one of Sodital substitutes.
In the intervention of preparation, dog is equipped with schrittmacher.
In first drug test (i.e. experiment starts) time of 21 days before, the schrittmacher of Biotronik company (Logos) is implanted in subcutaneous skin bag and via pacemaker electrode and contacted with heart, and pacemaker electrode enters into right ventricle through external jugular vein under rayed.
In the implantation of pacemaker, by 7F biopsy forceps (Cordis) via sheath introducer (Avanti+; Cordis) falling back in Femoral artery, and unlikely damage by after aortic valve, have mitral restriction infringement, monitored by echo cardiography and irradiation.After this, whole mouths that pass into are taken down, and dog is spontaneously waken up from narcosis.
At other 7 days (that is, before first drug test 14 days), start above-mentioned pacemaker, heart stimulates with the frequency of 220 impact/per minutes.
By using following instrument, stimulate the actual drug test of carrying out for 14 and 28 days after starting to test at pacemaker:
Alleviate and measure the bladder catheter of urine flow for bladder
Be connected to the ECG lead-in wire of each limit (for ecg measurement)
The Fluidmedic PE-300 pipe that fills NaCl inserts in femoral artery.This pipe is connected to pressure transmitter (Braun Melsungen, Melsungen, Germany) to measure systemic blood pressure
Millar Tip conduit (350 PC types, Millar Instruments, Houston, USA) inserts left atrium or is inserted in the port being fixed in carotid artery, for measuring cardiac hemodynamic
Swan-Ganz conduit (CCOmbo 7.5F, Edwards, Irvine, USA) inserts in pulmonary artery via jugular vein, for measuring cardiac output, and oxygen saturation, Ppa pulmonary artery pressure and central venous pressure
Braun ü le is arranged in cephalic vein, for pouring into Sodital, for liquid substitute and for blood sampling (mensuration of the blood plasma level of material or other clinical blood value)
Braun ü le is arranged in saphena, for pouring into fentanyl and the administration for material
Antidiuretic hormone (Sigma company) is with the perfusion of increased dosage amount, the at the most dosage of 4 mU/kg/ minutes.Then by this dosage test pharmacological agents.
If needed, original signal is exaggerated (Gould amplifier, Gould Instrument Systems, Valley View, USA) or (Edwards Vigilance-Monitor, Edwards, Irvine, USA) and be subsequently input in Ponemah system (DataSciences Inc, Minneapolis, USA) to evaluate.These signals, at whole experimental period record continuously, are further processed by counting process by this software, and average in 30 seconds.
C. the illustrative examples of pharmaceutical composition
Compound of the present invention changes into pharmaceutical preparation according to following manner:
tablet:
composition:
The compound of the present invention of 100 mg, the lactose (monohydrate) of 50 mg, the W-Gum (natural) of 50 mg, polyvinylpyrrolidone (the PVP 25) (BASF of 10 mg, Ludwigshafen, Germany) and the Magnesium Stearate of 2 mg.
Tablet weight 212 mg.Diameter 8 mm, radius-of-curvature 12 mm.
production method:
The mixture of compound of the present invention, newborn sugar and starch is used in 5% concentration solution (m/m) in water and carries out granulation.After dry, this particulate mixes with Magnesium Stearate 5 minutes.This mixture is by compressing (for tablet form, referring to above) with conventional tabletting machine.The guiding force of compression of compression use is 15,000 newton (kN).
suspension for oral use:
composition:
The compound of the present invention of 1000 mg, the ethanol (96%) of 1000 mg, the Rhodigel of 400 mg (xanthan gum, from FMC, Pennsylvania, USA obtains) and the water of 99 g.
The compounds of this invention of the single dosage of 100 mg is to give by the oral suspension of 10 ml.
production method:
Rhodigel is suspended in ethanol, then compound of the present invention is added in suspension.Under agitation add water.Stirring is proceeded approximately 6 hours, until the swelling end of Rhodigel.
solution for oral use:
composition:
The compound of the present invention of 500 mg, the poly(oxyethylene glycol) 400 of the polysorbate of 2.5 g and 97 g.The compounds of this invention of the single dosage of 100 mg is corresponding to the oral liquid of 20 g.
production method:
The compounds of this invention is under agitation suspended in the mixture of polyoxyethylene glycol and polysorbate.Stirring operation carries out continuously, until the compounds of this invention is fully dissolved.
intravenous injection (i.v.) solution:
The compounds of this invention for example, with in the solvent (isotonic saline solution, 5% glucose solution and/or 30% PEG 400 solution) that is dissolved in physiology lower than the concentration of saturation solubility and allows.Solution carries out sterile filtration and is assigned in aseptic, pyrogen-free injection vessel.

Claims (3)

1. the compound of following formula
Figure 2014100895952100001DEST_PATH_IMAGE001
5-(4-chloro-phenyl-)-4-[(2S)-3,3, the fluoro-2-hydroxypropyl of 3-tri-]-2,4-dihydro-3H-1,2,4-triazole-3-ketone.
2. the compound of following formula (III)
(III),
A is CH 2,
Q is N,
R 3be-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21huo – NR 26-SO 2-NR 27r 28–,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 12methyl,
R 13methyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 2-oxo-imidazole alkane-1-base or 2-oxo tetrahydropyrimidine-1 (2H)-basic ring,
R 19hydrogen,
R 20methyl or ethyl,
Or
R 19and R 20together with the atom being connected to them, form 2-oxo-1,3-
Figure 2014100895952100001DEST_PATH_IMAGE003
azoles alkane-3-base or 2-oxo-1,3- piperazine alkane-3-basic ring,
N is numeral 0 or 2,
R 21methyl,
R 26hydrogen,
R 27hydrogen,
R 28hydrogen,
R 4it is the group of following structural formula
Figure 2014100895952100001DEST_PATH_IMAGE004
Wherein
# is be connected to-C (R 5) (AR 3) tie point on N-,
R 22hydrogen, fluorine, chlorine and trifluoromethyl,
R 23hydrogen, fluorine, chlorine and trifluoromethyl,
Wherein this radicals R 22and R 23in at least one be not hydrogen,
R 5hydrogen or methyl,
R 29hydrogen.
3. descend the compound of formula V
(V),
A is CH 2,
Q is N,
R 3be-NR 8-C (=O)-R 9,-NR 10-SO 2-R 11,-SO 2-NR 12r 13,-O-C (=O)-NR 14r 15,-NR 16-C (=O)-NR 17r 18,-NR 19-C (=O)-OR 20,-S (=O) nr 21huo – NR 26-SO 2-NR 27r 28–,
Wherein
R 8hydrogen,
R 9methyl,
R 10hydrogen,
R 11methyl or ethyl,
R 12methyl,
R 13methyl,
R 14hydrogen or methyl,
R 15hydrogen, methyl or ethyl,
R 16hydrogen,
R 17hydrogen or methyl,
R 18hydrogen, methyl or ethyl,
Or
R 16and R 17together with the nitrogen-atoms being keyed to them, form 2-oxo-imidazole alkane-1-base or 2-oxo tetrahydropyrimidine-1 (2H)-basic ring,
R 19hydrogen,
R 20methyl or ethyl,
Or
R 19and R 20together with the atom being connected to them, form 2-oxo-1,3-
Figure 944923DEST_PATH_IMAGE003
azoles alkane-3-base or 2-oxo-1,3-
Figure 724660DEST_PATH_IMAGE003
piperazine alkane-3-basic ring,
N is numeral 0 or 2,
R 21methyl,
R 26hydrogen,
R 27hydrogen,
R 28hydrogen,
R 4it is the group of following structural formula
Figure 182186DEST_PATH_IMAGE004
Wherein
# is be connected to-C (R 5) (AR 3) tie point on N-,
R 22hydrogen, fluorine, chlorine and trifluoromethyl,
R 23hydrogen, fluorine, chlorine and trifluoromethyl,
Wherein this radicals R 22and R 23in at least one be not hydrogen,
R 5hydrogen or methyl,
R 29hydrogen.
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